Certain arylaliphatic and heteroaryl-aliphatic piperazinyl pyrazines and their use in the treatment of serotonin-related diseases

ABSTRACT

The invention relates to compounds of the general formula (I):  
                 
 
     wherein  
     Ar is optionally substituted aryl or heteroaryl;  
     A is (i) —O—, —S—, —SO 2 —, —NH—, (ii) a C 1-4 -alkyl- or C 1-6 -acyl-substituted nitrogen atom or (iii) a C 1-8 -alkylene chain or a heteroalkylene chain having 2 to 8 chain atoms, which optionally contains at least one unsaturation, and which may be substituted and/or contain a bridge to form a saturated or partially or fully unsaturated ring having 3-8 ring members;  
     B is —C(R 4 )(R 5 )—, —OC(R 4 )(R 5 )—, —N(R 6 )C(R 4 )(R 5 )—, —N(R 6 )—, —O—, —S— or —SO 2 —;  
     R is optionally substituted C 3-8 -cycloalkyl, aryl or heteroaryl;  
     R 1  is (i) a saturated or unsaturated azacyclic or aminoazacyclic ring, or a saturated diazacyclic or aminodiazacyclic ring, which has 4 to 7 ring members, or a saturated aminoazabicyclic, azabicyclic or diazabicyclic ring which has 7 to 10 ring members, which rings optionally are substituted in one or more positions, or a group —[C(R 4 )(R 5 )] x N(R 2a )(R 3a )];  
     R 2a , R 3a , R 4 , R 5 , R 6  and x are as defined in the claims, and n is 0 or 1;  
     and pharmaceutically acceptable salts, hydrates and prodrug forms thereof.  
     The compounds may be prepared by per se conventional methods and can be used for treating a human or animal subject suffering from a serotonin-related disorder, such as eating disorders, especially obesity, memory, disorders, schizophrenia, mood disorders, anxiety disorders, pain, sexual dysfunctions, and urinary disorders. The invention also relates to such use as well as to pharmaceutical compositions comprising a compound of formula (I).

[0001] The present application is a continuation-in-part application ofapplication Ser. No. 09/573,348, “Novel Compounds, Their Use andPreparation”, Attorney Docket No. 1614-233P, filed on May 19, 2000,which claims priority to provisional App. No. 60/137,527, filed on Jun.3, 1999; the entire contents of which are hereby incorporated byreference.

FIELD OF THE INVENTION

[0002] The present invention relates to novel compounds, topharmaceutical compositions comprising the compounds, to processes fortheir preparation, as well as to the use of the compounds for thepreparation of a medicament which particularly acts on the centralnervous system.

BACKGROUND OF THE INVENTION

[0003] Many diseases of the central nervous system are influenced by theadrenergic, the dopaminergic, and the serotonergic neurotransmittersystems. For example, serotonin has been implicated in a number ofdiseases and conditions which originate in the central nervous system. Anumber of pharmacological and genetic experiments involving receptorsfor serotonin strongly implicate the 5-HT_(2c) receptor subtype in theregulation of food intake (Obes. Res. 1995, 3, Suppl. 4, 449S-462S). The5-HT_(2c) receptor subtype is transcribed and expressed in hypothalamicstructures associated with appetite regulation. It has been demonstratedthat the non-specific 5-HT_(2c) receptor agonistm-chlorophenylpiperazine (mCPP), which has some preference for the5-HT_(2c) receptor, causes weight loss in mice that express the normal5-HT_(2c) receptor while the compound lacks activity in mice expressingthe mutated inactive form of the 5-HT_(2c) receptor (Nature 1995, 374,542-546). In a recent clinical study, a slight but sustained reductionin body weight was obtained after 2 weeks of treatment with mCPP inobese subjects (Psychopharmacology 1997, 133, 309-312). Weight reductionhas also been reported from clinical studies with other “serotonergic”agents (see e.g. IDrugs 1998, 1, 456-470). For example, the 5-HTreuptake inhibitor fluoxetine and the 5-HT releasing agent/reuptakeinhibitor dexfenfluramine have exhibited weight reduction in controlledstudies. However, currently available drugs that increase serotonergictransmission appear to have only a moderate and, in some cases,transient effects on the body weight.

[0004] The 5-HT_(2c) receptor subtype has also been suggested to beinvolved in CNS disorders such as depression and anxiety (Exp. Opin.Invest. Drugs 1998, 7, 1587-1599; IDrugs, 1999, 2, 109-120).

[0005] The 5-HT_(2c) receptor subtype has further been suggested to beinvolved in urinary disorders such as urinary incontinence (IDrugs.1999, 2, 109-120).

[0006] Compounds which have a selective effect on the 5-HT_(2c) receptormay therefore have a therapeutic potential in the treatment of disorderslike those mentioned above. Of course, selectivity also reduces thepotential for adverse effects mediated by other serotonin receptors.

[0007] Information Disclosure

[0008] U.S. Pat. No. 3,253,989 discloses the use of mCPP as an anorecticagent.

[0009] EP-A1-863 136 discloses azetidine and pyrrolidine derivativeswhich are selective 5-HT_(2c) receptor agonists having antidepressantactivity and which can be used for treating or preventingserotonin-related diseases, including eating disorders and anxiety.

[0010] EP-A-657 426 discloses tricyclic pyrrole derivatives havingactivity on the 5-HT_(2c) receptor and which inter alia may be used fortreating eating disorders.

[0011] EP-A-655 440 discloses 1-aminoethylindoles having activity on the5-HT_(2c) receptor and which may be used for treating eating disorders.

[0012] EP-A-572 863 discloses pyrazinoindoles having activity on'the5-HT_(2c) receptor and which may be used for treating eating disorders.

[0013] J. Med. Chem. 1978, 21, 536-542 and U.S. Pat. No. 4,081,542disclose a series of piperazinylpyrazines having centralserotonin-mimetic activity.

[0014] J. Med. Chem. 1981, 24, 93-101 discloses a series ofpiperazinylquinoxalines with central serotoninmimetic activity.

[0015] WO 00/12475 discloses indoline derivatives as 5-HT_(2b) and/or5-HT_(2c) receptor ligands, especially for the treatment of obesity.

[0016] WO 00/12510 discloses pyrroloindoles, pyridoindoles andazepinoindoles as 5-HT_(2c) receptor agonists, particluarly for thetreatment of obesity.

[0017] WO 00/12482 discloses indazole derivatives as selective, directlyactive 5-HT_(2c) receptor ligands, preferably 5-HT_(2c) receptoragonists, particularly for use as anti-obesity agents.

[0018] WO 00/12502 discloses pyrroloquinolines as 5-HT_(2c) receptoragonists, particularly for use as anti-obesity agents.

[0019] WO 00/12475 discloses indoline derivatives as 5-HT_(2b) and/or5-HT_(2c) receptor ligands especially for the treatment of obesity.

[0020] GB-B-1,457,005 discloses1-piperazinyl-2-[2-(phenyl)ethenyl]-quinoxaline derivatives whichexhibit anti-inflammatory activity.

[0021] Chem. Pharm. Bull. 1993, 41(10) 1832-1841 discloses 5-HT₃antagonists including 2-(4-methyl-1-piperazinyl)-4-phenoxyquinoxaline.

[0022] GB-B-1,440,722 discloses 2-(1′-piperazinyl)-quinoxaline compoundshaving pharmaceutical activity against depression.

[0023] WO 96/11920 discloses CNS-active pyridinylurea derivatives.

[0024] WO 95/01976 discloses indoline derivatives active as 5-HT_(2c)antagonists and of potential use in the treatment of CNS disorders.

[0025] WO 97/14689 discloses aryl-piperazine cyclic amine derivativeswhich are selective 5-HT_(1d) receptor antagonists.

[0026] WO 98/42692 discloses piperazines derived from cyclic amineswhich are selective antagonists of human 5-HT_(1a), 5-HT_(1d) and5-HT_(1b) receptors.

[0027] GB-B-1,465,946 discloses substituted pyridazinyl, pyrimidinyl andpyridyl compounds which are active as β-receptor blocking agents.

[0028] EP-A-711757 discloses[3-(4-phenyl-piperazin-1-yl)propylamino]-pyridine, pyrimidine andbenzene derivatives as α-adrenoceptor antagonists.

[0029] WO 99/03833 discloses aryl-piperazine derivatives which are 5-HT₂antagonists and 5-HT_(1a) receptor agonists and therefore are useful asremedies or preventives for psychoneurosis.

[0030] WO 96/02525 discloses aryl-piperazine-derived piperazidederivatives having 5-HT receptor antagonistic activity.

[0031] WO 99/58490 disloses aryl-hydronaphthalen-alkanamines which mayeffectuate partial or complete blockage of serotonergic 5-HT_(2c)receptors in an organism.

SUMMARY OF THE INVENTION

[0032] According to the present invention, a class of novel compoundshave been developed which bind to the 5-[HT_(2c) receptor (agonists andantagonists) and which therefore may be used for the treatment ofserotonin-related disorders.

[0033] In one aspect, the invention provides novel compounds of thegeneral formula

[0034] wherein

[0035] Ar is aryl or heteroaryl which may be independently substitutedin one or more positions by C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,C₁₋₆-acyl, C₁₋₆-alkylsulphonyl, cyano, nitro, hydroxy, C₂₋₆-alkenyl,C₂₋₆-alkynyl, fluoromethyl, difluoromethyl, trifluoromethyl,difluoromethoxy, trifluoromethoxy, difluoromethylthio,trifluoromethylthio, halogen, —N(R₂)(R₃), aryl, aryloxy, arylthio,aryl-C₁₋₁₄-alkyl, aryl-C₂₋₄-alkenyl, aryl-C₂₋₄-alkynyl, heterocyclyl,heterocyclyloxy, heterocyclylthio or heterocyclyl-C₁₋₄-alkyl, whereinany aryl and heterocyclyl residues as substituents or part ofsubstituents on aryl or heteroaryl in turn may be substituted in one ormore positions independently of each other by halogen, C₁₋₆-alkyl,C₁₋₆-alkoxy, C₁₋₆-alkylthio, C₁₋₆-acyl, C₁₋₆-alkylsulphonyl, nitro,trifluoromethyl, trifluoromethylthio, cyano, hydroxy, amino,C₁₋₆-alkylamino, di(C₁₋₆-alkyl)amino or C₁₋₆-acylamino;

[0036] A is (i) —O—, —S—, —SO₂— or —NH—; (ii) a C₁₋₄-alkyl-substitutednitrogen atom, or (iii) a C₁₋₈-alkylene chain or a heteroalkylene chainhaving 2 to 8 chain atoms, which optionally contains one or moreunsaturations, wherein C₁₋₈-alkylene and heteroalkylene may beindependently substituted in one or more positions by C₁₋₄-alkyl or oxo,and wherein two juxtaposed or spaced chain atoms in C₁₋₈-alkylene orheteroalkylene optionally are joined through an alkylene bridge having 1to 5 chain carbon atoms or a heteroalkylene bridge having 2 to 5 chainatoms, or two spaced chain atoms in C₁₋₈-alkylene or heteroalkyleneoptionally are joined through a bridging bond, to form a saturated orpartially or fully unsaturated carbocyclic or heterocyclic ring having 3to 8 ring members;

[0037] B is —C(R₄)(R₅)—, —OC(R₄)(R₅)—, —N(R₆)C(R₄)(R₅)—, —N(R₆)—, —O—,—S— or —SO₂—;

[0038] R is C₃ g-cycloalkyl, aryl or heteroaryl, each of which may besubstituted in one or more positions independently of each other byC₁₋₆-alkyl. C₁₋₆-alkoxy, fluoro-C₁₋₆-alkoxy, 2,2,2-trifluoroethoxy,C₃₋₅-alkynyloxy, C₃₋₅-alkenyloxy, dimethylamino-C₁₋₆-alkoxy,methylamino-C₁₋₆-alkoxy, ° C₁₋₆-alkylthio, fluoromethyl, difluoromethyl,trifluoromethyl, fluoromethylthio, difluoromethoxy, difluoromethylthio,trifluoromethoxy, trifluoromethylthio, halogen, hydroxy, nitro, cyano,trifluoromethylsulphonyloxy, C₁₋₆-alkylsulphonamido, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₁₋₆-acyl, C₁₋₆-alkylcarbonyl-C₁₋₆-alkyl,C₁₋₆-alkylsulphonyl, C₁₋₆-alkylsulphonyloxy, C₁₋₆-alkoxy-C₁₋₆-alkyl,C₁₋₆-alkoxycarbonyl, C₁₋₆-alkoxycarbonyl-C₁₋₆-alkyl,C₁₋₆-acyloxy-C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, hydroxy-C₁₋₆-alkoxy,C₁₋₆-alkoxy-C₁₋₆-alkoxy, C₁₋₆-alkoxy-C₁₋₆-alkylthio,hydroxy-C₁₋₆-alkylthio, heteroaryl-C₁₋₆-alkylthio, aryl-C₁₋₆-alkylthio,C₁₋₆-alkoxy-C₁₋₆-alkylamino, N—(C₁₋₆-alkoxy-C₁₋₆-alkyl)-N-methylamino,C₃₋₆-cycloalkyl-C₁₋₆-alkoxy, aryl-C₁₋₆-alkoxy, heterocyclyl-C₁₋₆-alkoxy,C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyloxy, aryl, aryloxy, arylthio,arylsulphonyl, aryl-C₁₋₆-acyl, aryl-C₁₋₆-alkyl, aryl-C₂₋₆-alkenyl,aryl-C₂₋₆-alkynyl, heterocyclyl-C₁₋₆-alkyl, heterocyclyl-C₂₋₆-alkenyl,heterocyclyl-C₂₋₆-alkynyl, heterocyclyl, heterocyclyloxy,heterocyclylthio, heterocyclylsulphonyl, heterocyclylamino,heterocyclyl-C₁₋₆-acyl, —N(R₂)(R₃), —CON(R₇)(R₈) or, when R isoptionally substituted C₃₋₈-cycloalkyl, oxo, wherein any cycloalkyl,aryl and heterocyclyl residues as substituents on C₃₋₈-cycloalkyl, arylor heteroaryl or as part of substituents on C₃₋₈-cycloalkyl, aryl orheteroaryl in turn may be substituted in one or more positionsindependently of each other by C₁₋₄-alkyl, C₁₋₄-alkoxy,methanesulphonamido, C₁₋₄-alkylthio, C₁₋₄-alkylsulphonyl, C₁₋₄-acyl,heterocyclyl, heterocyclyloxy, heterocyclylthio, aryloxy, arylthio,fluoromethyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio,halogen, hydroxy, nitro, cyano, N(R₂)(R₃) or, for C₃₋₈-cycloalkyl andpartially or fully saturated heterocyclyl, oxo or hydroxy;

[0039] R₁ is (i) a saturated or unsaturated azacyclic or aminoazacyclicring, or a saturated diazacyclic or aminodiazacyclic ring, which has 4to 7 ring members, or a saturated aminoazabicyclic, azabicyclic ordiazabicyclic ring which has 7 to 10 ring members, which mono- orbicyclic rings may be mono- or disubstituted in one or more positionsindependently of each other by, preferably bound to a carbon atom.C₁₋₄-alkyl. C₁₋₄-alkoxy, fluoromethyl, trifluoromethyl, difluoromethyl,hydroxymethyl or methoxymethyl or —N(R₆)₂, or, preferably bound to aring nitrogen atom, hydroxy, 2-hydroxyethyl or 2-cyanoethyl, or, boundto a ring nitrogen atom, C₁₋₆-acyl. C₁₋₄-alkoxycarbonyl ortetrahydropyran-2-yl, and wherein a saturated azacyclic ring may containa further heteroatom, selected from oxygen and sulphur; or (ii) a group—[C(R₄)(R₅)]_(x)N(R_(2a))(R_(3a));

[0040] R₂ and R₃ independently of each other are hydrogen, C₁₋₆-alkyl,C₁₋₆-acyl, —CON(R₇)(R₈), aryl, heterocyclyl, aryl-C₁₋₆-alkyl,heterocyclyl-C₁₋₆-alkyl, aryl-C₁₋₆-acyl or heterocyclyl-C₁₋₆-acyl,wherein any aryl and heterocyclyl residues in turn may be substituted inone or more positions independently of each other by halogen,C₁₋₄-alkyl, C₁₋₄-alkoxy, C₁₋₄-alkylthio, C₁₋₄-alkylsulphonyl,methanesulphonamido, nitro, cyano, hydroxy, trifluoromethyl,trifluoromethoxy, trifluoromethylthio or —N(R₂)(R₃); or R₂ and R₃together with the nitrogen atom to which they are bound form a saturatedheterocyclic ring having 4-7 ring members and optionally containing afurther heteroatom, which ring may be substituted by C₁₋₆-alkyl,C₁₋₆-alkoxy, oxo or hydroxy;

[0041] R_(2a) and R_(3a) independently of each other are hydrogen,methyl or ethyl, or R_(2a) and R_(3a) together with the nitrogen atom towhich they are bound form a pyrrolidine, piperazine, morpholine,thiomorpholine or piperidine ring;

[0042] R₄ and R₅ independently of each other, and independently on eachsubstituted carbon atom, are hydrogen or C₁₋₆-alkyl;

[0043] R₆ is hydrogen or C₁₋₆-alkyl;

[0044] R₇ and R₈ independently of each other are hydrogen, C₁₋₆-alkyl,aryl, heteroaryl, aryl-C₁₋₄-alkyl or heteroaryl-C₁₋₄-alkyl, wherein aryland heteroaryl residues in turn may be substituted in one or morepositions independently of each other by halogen, C₁₋₆-alkyl,C₁₋₆-alkoxy, C₁₋₆-alkylthio, C₁₋₆-alkylsulphonyl, methanesulphonamido,nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy,trifluoromethylthio or —N(R₂)(R₃); or R₇ and R₈ together with thenitrogen atom to which they are bound form a saturated heterocyclic ringhaving 4-7 ring members and optionally containing a further heteroatom;

[0045] n is 0 or 1, and

[0046] x is 2, 3 or 4;

[0047] with the proviso that (i) when -A-R is phenoxy or phenylthio,then Ar is other than quinoxalinyl or pyridyl, and (ii) when A isethenylene, then Ar is other than quinoxalinyl;

[0048] and pharmaceutically acceptable salts, hydrates, geometricalisomers, tautomers, optical isomers, N-oxides and prodrug forms thereof.

[0049] A limited group of compounds of the invention comprise compoundsof formula (I) as defined above but with the further proviso that whenAr is optionally substituted phenyl, pyridyl or quinoxalinyl, then A isa group -Het-CH(R₆)—CH(R₆)-Het-, where each Het independently isselected from O, S and N(R₆), and R₆ is as defined above.

[0050] In case the compounds of formula (I) can be in the form ofoptical isomers, the invention comprises the racemic mixture as well asthe individual enantiomers as such.

[0051] In case the compounds of formula (I) contain groups which mayexist in tautomeric forms, the invention comprises the tautomeric formsof the compounds as well as mixtures thereof, e.g, a 2-hydroxypyridineand its tautomer 1H-2-pyridone.

[0052] In case the compounds of formula (I) can be in the form ofgeometrical isomers, the invention comprises the geometrical isomers aswell as mixtures thereof.

[0053] In another aspect, the invention provides the compounds accordingto formula (I) above for use in therapy.

[0054] Still another aspect of the invention provides a pharmaceuticalcomposition comprising a compound according to formula (I) above as theactive ingredient, preferably together with a pharmaceuticallyacceptable carrier and, if desired, other pharmacologically activeagents.

[0055] In yet another aspect, the invention provides a method for thetreatment of a human or animal subject suffering from aserotonin-related disease, particularly 5-HT2 receptor-related,especially eating disorders, particularly obesity; memory disorders,schizophrenia, mood disorders, anxiety disorders, pain, sexualdysfunctions, and urinary disorders.

[0056] Another aspect of the invention provides the use of the compoundsaccording to formula (I) above for the manufacture of a medicament forthe treatment of a serotonin-related disease, particularly 5-HT₂receptor-related, especially eating disorders, particularly obesity;memory disorders; schizophrenia, mood disorders, anxiety disorders,pain, sexual dysfunctions, and urinary disorders.

[0057] Still another aspect of the invention provides methods for thepreparation of the compounds according to formula (I) above.

DETAILED DESCRIPTION OF THE INVENTION

[0058] First, the various terms used, separately and in combinations, inthe above definition of the compounds having the general formula (I)will be explained.

[0059] By “heteroatom” is meant nitrogen, oxygen, sulphur, and inheterocyclic rings (including heteroaromatic as well as saturated andpartially saturated heterocyclic rings), also selenium.

[0060] The term “aryl” is intended to include aromatic rings (monocyclicor bicyclic) having from 6 to 10 ring carbon atoms, such as phenyl,naphthyl and 1,2,3,4-tetrahydronaphthyl (substitutions may be in anyring).

[0061] The term “heteroaryl” means a monocyclic, bi- or tricyclicaromatic ring system (only one ring need to be aromatic, andsubstitutions may be in any ring) having from 5 to 14, preferably 5 to10 ring atoms (mono- or bicyclic), in which one or more of the ringatoms are other than carbon, such as nitrogen, sulphur, oxygen andselenium. Examples of such heteroaryl rings are pyrrole, imidazole,thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole,isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine,pyrazole, triazole, tetrazole, chroman, isochroman, coumarin, quinoline,quinoxaline, isoquinoline, phthalazine, cinnoline, quinazoline, indole,isoindole, indoline, isoindoline, benzothiophene, benzofuran,2,3-dihydrobenzofuran, isobenzofuran, benzoxazole, 2,1,3-benzoxadiazole,benzothiazole, 2,1,3-benzothiadiazole, 2,1,3-benzoselenadiazole,benzimidazole, indazole, 2,3-dihydro-1,4-benzodioxine, indane,1,3-benzodioxole, 1,2,3,4-tetrahydroquinoline,3,4-dihydro-2H-1,4-benzoxazine, 1,5-naphthyridine, 1,8-naphthyridine,acridine, fenazine, xanthene, 3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazine,and 2,3-dihydro-1,4-benzoxathiine. The heteroaryl ring may be linked tothe divalent group A in formula (I) via a carbon or nitrogen atomthereof. If a bi- or tricyclic ring is substituted, it may besubstituted in any ring.

[0062] The term “heteroalkylene” means an alkylene group which containsa terminal heteroatom at one or both ends and/or one or more carbonchain-interrupting heteroatom(s) selected from N, O and S. The number ofheteroatoms is at least one, and usually from one to three, especiallyone or two. When heteroalkylene is substituted, it is usuallysubstituted at a carbon atom by C₁₋₄-alkyl or oxo, but it mayalternatively or additionally be substituted at a nitrogen by C₁₋₄-alkylor at a sulphur atom by oxo (S═O or O═S═O), if present.

[0063] The term “heterocyclyl” is intended to include fully unsaturated(i.e, aromatic) as well as partially and fully saturated mono-, bi- andtricyclic rings having from 4 to 14, preferably 4 to 10 ring atoms, andcontaining one or more heteroatoms selected from oxygen, sulphur andnitrogen, such as, for example, the heteroaryl groups mentioned above aswell as their corresponding partially saturated or fully saturatedheterocyclic rings. Exemplary saturated heterocyclic rings areazetidine, pyrrolidine, piperidine, piperazine, morpholine andthiomorpholine.

[0064] C₁₋₆-alkyl, which may be straight or branched, is preferablyC₁₋₄-alkyl.

[0065] Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl,butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and isohexyl.C₁₋₆-alkoxy, which may be straight or branched, is preferablyC₁₋₄-alkoxy.

[0066] Exemplary alkoxy groups include methoxy, ethoxy, propoxy,isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy,hexyloxy, and isohexyloxy.

[0067] C₂₋₆-alkenyl, which may be straight or branched, is preferablyC₂₋₄-alkenyl, e.g.

[0068] 1-propenyl, 2-propenyl, vinyl. C₂₋₆-alkynyl, which may bestraight or branched, is preferably C₂₋₄-alkynyl, e.g, propargyl,ethynyl.

[0069] C₃₋₈-cycloalkyl is preferably C₄₋₇-cycloalkyl. Exemplarycycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

[0070] C₁₋₆-acyl may be saturated or unsaturated and is preferablyC₁₋₄-acyl. Exemplary acyl groups include formyl, acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, butenoyl (e.g. 3-butenoyl),hexenoyl (e.g. 5-hexenoyl).

[0071] C₁₋₈-alkylene (wherein 1-8 is the number of chain carbon atoms)and heteroalkylene having 2 to 8 chain atoms, which may contain one ormore unsaturations (double and/or triple bonds), are preferablyC₁₋₄-alkylene and heteroalkylene of 2 to 4 chain atoms, respectively.Exemplary alkylene groups include methylene, ethylene, propylene,butylene and their isomers (e.g. 1,3-butylene, 2-methyl-1,3-propylene).

[0072] Exemplary heteroalkylene groups include oxymethylene (andmethylenoxy), oxyethylene (and ethylenoxy), oxypropylene (andpropylenoxy), oxybutylene (and butylenoxy), ethylenedioxy,propylenedioxy, butylenedioxy, oxyallyl (and allyloxy), etc. Anexemplary alkyl-substituted heteroalkylene group is methylethylenedioxy.

[0073] Hydroxy-C₁₋₆-alkyl may be straight or branched. Exemplaryhydroxyalkyl groups include hydroxymethyl, 1-hydroxyethyl,2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxybutyl,3-hydroxybutyl, 4-hydroxybutyl.

[0074] Exemplary aryl-C₁₋₆-acyl groups include benzoyl, 1-naphthoyl,2-naphthoyl, cinnamoyl and phenylacetyl.

[0075] Exemplary C₁₋₆-alkylcarbonyl-C₁₋₆-alkyl groups include2-oxobutyl.

[0076] Exemplary C₁₋₆-alkoxy-C₁₋₆-alkyl groups include 2-ethoxyethyl.

[0077] Exemplary C₁₋₆-alkoxycarbonyl-C₁₋₆-alkyl groups includeethoxycarbonylbutyl.

[0078] Exemplary C₁₋₆-acyloxy-C₁₋₆-alkyl groups includepropanoyloxypropyl.

[0079] Exemplary saturated and unsaturated (partially and fully)azacyclic and saturated azabicyclic rings include azetidine,pyrrolidine, piperidine, morpholine, hexahydroazepine,tetrahydropyridine, pyridine and 1-azabicyclo[2.2.2]octane. Theazacyclic and azabicyclic rings are coupled via a ring carbon atom whenn=0.

[0080] Exemplary saturated and unsaturated aminoazacyclic rings includeaminopiperidine (e.g. 4-aminopiperidine), aminoazetidine (e.g.3-aminoazetidine), aminopyrrolidine (e.g. 3-aminopyrrolidine), andaminopyridine (e.g. 4-aminopyridine). The aminoazacyclic rings arepreferably coupled to B or Ar in formula (I) via either the aza nitrogenatom or the amino nitrogen atom. An example of a saturatedaminoazabicyclic ring is 3-aminoazabicyclo[2.2.2]octane, and thecoupling is preferably via the 3-amino nitrogen atom.

[0081] An example of a saturated aminodiazacyclic ring is1-aminopiperazine, and the coupling is preferably via either the 4-azanitrogen atom or the 1-amino nitrogen atom.

[0082] Exemplary saturated diazacyclic rings include piperazine andhomopiperazine, and an example of a diazabicyclic ring isdiazabicyclo[2.2.1]heptane. The diazacyclic and diazabicyclic rings arepreferably coupled via one of the ring nitrogens.

[0083] The group —[C(R₄)(R₅)]_(x)N(R_(2a))(R_(3a)) is preferably linkedto Ar in formula (I) via a heteroatom (i.e, when n=1 and B is oxygen,nitrogen or sulphur).

[0084] As indicated by the expression “independently for eachsubstituted carbon atom” with regard to substituents R₄ and R₅, eachindividual carbon atom in the chain —[C(R₄)(R₅)]_(x)— may be differentlysubstituted than the adjacent carbon atom(s). An exemplary chain, wereinx=3, illustrating this is —CH(CH₃)—CH₉—C(CH₃)(CH₃)—.

[0085] Halogen includes fluorine, chlorine, bromine and iodine.

[0086] Where it is stated above that aryl, heteroaryl and heterocyclylresidues may be substituted, this applies to aryl, heteroaryl andheterocyclyl per se as well as to any combined groups containing aryl,heteroaryl or heterocyclyl residues, such as aryl-C₁₋₆-acyl,heteroaryl-C₂₋₄-alkenyl, heterocyclylthio, etc.

[0087] The term “N-oxides” means that one or more nitrogen atoms, whenpresent in a compound, are in N-oxide form (NO).

[0088] The term “prodrug forms” means a pharmacologically acceptablederivative, such as an ester or an amide, which derivative isbiotransformed in the body to form the active drug. Reference is made toGoodman and Gilman's, The Pharmacological basis of Therapeutics, 8^(th)ed., McGraw-Hill, Int. Ed. 1992, “Biotransformation of Drugs, p. 13-15.

[0089] “Pharmaceutically acceptable” means being useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes being useful forveterinary use as well as human pharmaceutical use.

[0090] “Pharmaceutically acceptable salts” mean salts which arepharmaceutically acceptable, as defined above, and which possess thedesired pharmacological activity. Such salts include acid addition saltsformed with organic and inorganic acids, such as hydrogen chloride,hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid,acetic acid, glycolic acid, maleic acid, malonic acid, oxalic acid,toluenesulphonic acid, methanesulphonic acid, trifluoroacetic acid,fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid,ascorbic acid and the like.

[0091] “A” in formula I is preferably a C₂₋₈-alkylene chain or aheteroalkylene chain having at least two chain atoms.

[0092] More preferably, “A” in formula I is a divalent group of thegeneral formula (II):

[0093] wherein

[0094] R₉, R₁₀, R₁₁ and R₁₂ independently of each other, andindependently for each substituted carbon atom, are hydrogen,C₁₋₄-alkyl, trifluoromethyl or oxo;

[0095] X is —C(R₁₃)(R₁₄)—, —O—, —S—, —SO₂— or —N(R₁₅)—;

[0096] Y is independently —C(R₁₆)(R₁₇)—, —O—, —S—, —SO₂— or —N(R₁₅)—;

[0097] Z is independently —C(R₁₈)(R₁₉)-, —O—, —S—, —SO₂— or —N(R₁₅)—;

[0098] R₁₃, R₁₄, R₁₆, R₁₇, R₁₈ and R₁₉, independently of each other, andindependently for each substituted carbon atom, are hydrogen, C₁₋₄-alkylor trifluoromethyl or oxo; or two of R₁₃, R₁₄, R₁₆, R₁₇, R₁₈ and R₁₉together represent an interconnecting bond or an alkylene bridge of 1 to5 chain carbon atoms or a heteroalkylene bridge of 2 to 5 chain atoms toform, together with the atom(s) to which they are bound, a cyclicstructure having 3-8 ring members;

[0099] R₁₅ is hydrogen, C₁₋₄-alkyl or C₁₋₆-acyl;

[0100] o, p, q and r independently of each other are 0 to 3; and

[0101] the four broken lines independently of each other represent anoptional carbon-carbon bond;

[0102] with the provisos (i) that A does not contain two juxtaposedheteroatoms O or S in an open chain, and (ii) that o, p, q and rtogether are not more than 8.

[0103] The expression “independently for each substituted carbon atom”means that if in formula (II) the integers o and/or q are 2 or 3, eachcarbon atom in question may be differently substituted. Thus, in thecase of R₉ and R₁₀, for example, if o is 2 or 3, for each of the two orthree carbons atoms, the meanings of R₉ and R₁₀ may be chosenindependently of the meanings for R₉ and R₁₀ on the other two or threecarbon atoms. For example, when o=2, the coupling to X is via a singlebond, and R₉ and R₁₀ are independently selected from hydrogen andmethyl, then e.g. R₉ may be hydrogen and R₁₀ methyl on the first carbonatom and both R₉ and R₁₀ may be hydrogen oil the second carbon atom,i.e, the group 1-methylethylene. If R₉ and R₁₀ on the first carbon atomare hydrogen and, on the second carbon atom R₉ is hydrogen and R₁₀ ismethyl, the group 2-methylethylene is obtained. Exemplary groups foro=3, when R₉ and R₁₀ are independently selected from e.g, hydrogen,methyl and oxo, are 2-oxo-1,3-butanediyl;1-oxo-2-methyl-1,3-propanediyl, 1-oxo-1,3-butanediyl and1-oxo-2-methyl-1,3-butanediyl. The corresponding applies, of course,also to Y and Z in formula (II) when Y and Z are other than —O— or —S—and the integers p and r, respectively, are 2 or 3.

[0104] When formula (II) contains a carbon-carbon double bond(s) and/ora triple bond(s), one or both substituents on each participating carbonatom is, of course, omitted (for double bonds: R₉ and R₁₃ and/or R₁₁ andR₁₆, respectively; and for triple bonds: R₉, R₁₀, R₁₃ and R₁₄ and R₁₁,R₁₂, R₁₆ and R₁₇, respectively).

[0105] In a preferred embodiment, A in formula (I) is a group-Het-CH(R₆)—CH(R₆)-Het-, where each Het independently is selected fromO, S and N(R₆), and R₆ is as defined above, preferably hydrogen ormethyl, particularly hydrogen.

[0106] The presently most preferred group A is —O—CH₂—CH₂—O—. Otherpreferred groups A include —S—CH₂—CH₂—O—, —O—CH₂—CH₂—S—, and—O—CH₂—CH₂—CH₂—.

[0107] In another preferred embodiment, A is —O—CH₂— and R is optionallysubstituted heteroaryl, e.g. 2,3-dihydro-1,4-benzodioxine,3,4-dihydro-2H-1,4-benzoxazine, 2,3-dihydro-1,4-benzoxathiine,quinoline, benzofuran, 3,4-dihydro-2H-pyrido(3,2-b)-1,4-oxazine.

[0108] R in formula (I) is preferably optionally substituted aryl orheteroaryl. When R is aryl, it is preferably phenyl which is substitutedor unsubstituted, preferably substituted. When R is substituted phenyl,it is preferably substituted in the meta-position. When R is heteroaryl,it is preferably selected from pyridine, isoquinoline, quinoline,quinoxaline, 2,3-dihydro-1,4-benzodioxine, benzoxazole,2,1,3-benzothiadiazole, coumarin, 3,4-dihydro-2H-1,4-benzoxazine andquinazoline. Especially R is a substituted (especially meta-substituted)phenyl ring, or an unsubstituted or substituted pyridine ring.

[0109] Ar in formula (I) is preferably unsubstituted or substitutedpyrazine, quinoxaline., 1,2,5-thiadiazole, pyridyl or phenyl.

[0110] When Ar is substituted it is usually mono- or (independently)di-substituted. Preferred substituents on Ar are selected fromC₁₋₄-alkyl. C₁₋₄-alkoxy. C₁₋₄-alkylthio. C₁₋₄-alkylsulphonyl, cyano,hydroxy, C₂₋₄-alkenyl, C₂₋₄-alkynyl, trifluoromethyl,trifluoromethylthio, halogen, amino, methylamino, dimethylamino,acetamido, aryl, aryloxy, arylthio, heterocyclyl, heterocyclyloxy,heterocyclylthio, wherein any aryl and heterocyclyl residues in turn maybe substituted in one or more positions independently of each other byhalogen, methyl, methoxy, methylthio, methylsulphonyl, nitro,trifluoromethyl, cyano, hydroxy, amino, methylamino and dimethylamino oracetamido.

[0111] R₁ in formula (I) is preferably a saturated diazacyclic ring,especially piperazine, unsubstituted or substituted by C₁₋₄-alkyl, e.g,mono-substituted, particularly by methyl (at any position).

[0112] The integer n in formula (I) is preferably 0. When n=1, B ispreferably —N(R₆)—, —O—, —S— or —SO₂—, where R₆ is as defined above.

[0113] The integer o in formula (II) is preferably 2.

[0114] The integer p in formula (II) is preferably 1.

[0115] The integer q in formual (II) is preferably 0.

[0116] The integer r in formual (II) is preferably 0.

[0117] X, Y and Z are preferably oxygen.

[0118] R₉ to R₁₂ are preferably hydrogen.

[0119] In a preferred subgroup of compounds of formula 1, Ar is apyrazine ring, i.e. compounds of formula (Ia):

[0120] wherein

[0121] R₂₀ and R₂₁ independently of each other are hydrogen, C₁₋₄-alkyl,C₁₋₄-alkoxy, C₁₋₄-alkylthio, C₁₋₄-acyl, C₁₋₄-alkylsulphonyl, cyano,nitro, hydroxy. C₂₋₄-alkenyl. C₂₋₄-alkynyl, trifluorioethyl,tritluorometlhoxy, trifluoromethyltlio, halogen, aminio, dimethylamino,methylamiinio, acetamiido, aryl, aryloxy, arylthio, heterocyclyl,heterocyclyloxy or heterocyclylthio, wherein any aryl and heterocyclylresidues in turn may be substituted in one or more positionsindependently of each other by halogen, methyl, methoxy, methylthio,methylsulphonyl, nitro, cyano, hydroxy, trifluoromethyl, amino,methylamino, dimethylamino or acetamido; or —R₂₀ and R₂₁ together withthe carbon atoms to which they are bound form a 5- or 6-memberedaromatic or heteroaromatic ring, which optionally is independentlysubstituted in one or more positions by halogen, methyl, methoxy,methylthio, methylsulphonyl, nitro, cyano, hydroxy, trifluoromethyl,trifluoromethylthio, amino, methylamino, dimethylamino or acetamido;

[0122] m₁ and m₂ are independently of each other 0 or 1; and

[0123] A, B, R, R₁ and n are as defined above.

[0124] When R₂₀ and R₂₁ in formula (Ia) form a 5- or 6-membered aromaticor heteroaromatic ring together with the pyrazine ring carbons, such aring may, for example, be selected from the aryl and heteroaryl ringsmentioned above.

[0125] R₂₀ and R₂₁ are preferably (independently) hydrogen, halogen ormethyl. When R₂₀ and R₂₁ form a ring together with the ring carbons towhich they are bound, such a ring is preferably benzene (to givequinoxaline) or thiophene (to give thieno[3,4-b]pyrazine). Whensubstituted, the rings are preferably mono- or (independently)disubstituted, such as by halogen or methyl.

[0126] The integers m₁ and m₂ are preferably both zero (i.e, thepyrazine nitrogens are not in oxidized form).

[0127] A subgroup of the compounds of formula (Ia) consists of compoundsof formula (Ib):

[0128] wherein:

[0129] X₁ and Y independently are —O—, —S— or —N(R₂₇)—;

[0130] R_(a) is aryl or heteroaryl optionally substituted as defined forR in claim 1;

[0131] R₂₀ and R₂₁ are as defined in claim 11;

[0132] R₂₂ is hydrogen, hydroxy, C₁₋₄-alkyl, C₃₋₄-alkenyl, C₁₋₄-acyl,C₁₋₄-alkoxycarbonyl, 2-hydroxyethyl, 2-cyanoethyl ortetrahydropyran-2-yl;

[0133] R₂₃ and R₂₄ independently of each other are hydrogen, C₁₋₄-alkyl,hydroxymethyl, C₁₋₄-alkoxymethyl or fluoromethyl;

[0134] R₂₅ is hydrogen or C₁₋₄-alkyl;

[0135] R₂₆ is hydrogen, C₁₋₄-alkyl or is linked to a carbon atom inR_(a) adjacent to the atom binding to Y₁ to form (together with thecarbon atom to which it is bound, Y₁ and the two atoms in R_(a)) a 5- or6-membered ring which may contain an additional heteroatom,

[0136] R₂₇ is hydrogen or C₁₋₄-alkyl, preferably methyl or ethyl; and

[0137] y and z independently of each other are 1 or 2.

[0138] Exemplary ring systems formed when R₂₆ is linked to R_(a) are2,3-dihydro-1,4-benzodioxine, 3.4-dihydro-2H-1,4-benzoxazine,2,3-dihydro-1,4-benzoxathiine and benzofuran.

[0139] In formula (Ib), R₂₂ is preferably hydrogen, and R₂₃ and R₂₄ arepreferably C₁₋₄-alkyl, especially methyl, or hydrogen. Particularly, R₂₃is methyl (especially in the 2-position of the piperazine ring; andpreferably with (R)-configuration at the chiral carbon atom), z is 1 andR₂₄ is hydrogen. When R₂₃ or R₂₄ are other than hydrogen and at leastone of y and z is 2, or y and z both are 1, then R₂₃ or R₂₄respectively, may be on the same or different carbon atoms.

[0140] R₂₅ is preferably hydrogen.

[0141] Presently preferred compounds of the general formula (I) aboveare:

[0142] 2-(2-Phenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether

[0143] 2-(2-Fluorophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether

[0144] 2-(3-Cyanophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether

[0145] 2-(3-Methoxyhenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether

[0146] 2-[3-(2-hydroxyethoxy)phenoxy]ethyl 3-(1-piperazinyl)-2-pyrazinylether

[0147] 2,3-Dihydro-1,4-benzodioxin-2-ylmethyl3-(1-piperazinyl)-2-pyrazinyl ether

[0148] 2-(2-Methoxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether

[0149] 2-(2,5-Difluorophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether

[0150] 2-(3,5-Dimethoxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether

[0151]2-(3,4-Dihydro-2H-pyrido[3,2-b]-1,4-oxazin-2-ylmethoxy)-3-(1-piperazinyl)pyrazine

[0152] 2-Methyl-1-[3-(2-phenoxyethoxy)-2-pyrazinyl]piperazine,particularly the (R)-enantiomer thereof

[0153] 2-Methyl-1-{3-(2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine,particularly the (R)-enantiomer thereof

[0154] 2-(Quinazolinyl-8-yloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether

[0155] 2-(Isoquinolinyl-5-yloxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether

[0156]2-[2-(3-Pyridinyloxy)ethoxy]-3-(1-piperazinyl)-6,7-difluoroquinoxaline

[0157]2-[2-(3-Pyridinyloxy)ethoxy]-3-(1-piperazinyl)thieno[3,4-b]pyrazine

[0158]2-(3,4-Dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-(1-piperazinyl)pyrazine

[0159]2-Methyl-1-{3-[2-(2-amino-8-quinolinyloxy)ethoxy]-2-pyrazinyl}piperazine,particularly the (R)-enantiomer thereof

[0160] 1-{3-[2-(2-Methoxy-3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine

[0161]2-Methyl-1-{3-[2-(2-methoxy-3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine,particularly the (R)-enantiomer thereof.

[0162]2-{2-[(2-Chloro-3-pyridinyl)oxy]ethoxy)}-3-(1-piperazinyl)pyrazine,

[0163]2-{2-[(2-Ethoxy-3-pyridinyl)oxy]ethoxy}-3-(1-piperazinyl)pyrazine,

[0164]1-(3-{2-[(2-Ethoxy-3-pyridinyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine,particularly the (R)-enantiomer thereof.

[0165]2-(2-{[2-(Methylsulfanyl)-3-pyridlyl]oxy}ethoxy)-3-(1-piperazinyl)pyrazine.

[0166]2-Methyl-1-[3-(2-{[2-(methylsulfanyl)-3-pyridinyl]oxy}ethoxy)-2-pyrazinyl]piperazinie,particularly the (R)-enantiomer thereof,

[0167] 2-{2-[(2-Bromo-3-pyridinyl)oxy]ethoxy}-3-(1-piperazinyl)pyrazine,

[0168]1-(3-{2-[(2-Bromo-3-pyridinyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine,particularly the (R)-enantiomer thereof,

[0169]2-(1-piperazinyl)-3-{2-(3-[2-(2-pyridinyl)ethoxy]phenoxy}ethoxy)pyrazine,

[0170]2-(2-{3-[2-(4-Methyl-1,3-thiazol-5-yl)ethoxy]phenoxy}ethoxy)-3-(1-piperazinyl)pyrazine,

[0171]2-(1-piperazinyl)-3-{2-[3-(tetrahydro-3-furanylmethoxy)phenoxy]ethoxy}pyrazine,

[0172]2-(1-piperazinyl)-3-{2-[3-(tetrahydro-3-furanyloxy)phenoxy]ethoxy}pyrazine,

[0173]1-{2-[3-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)phenoxy]ethyl}-2-pyrrolidinone,

[0174]2-{2-[3-(2-Methoxyethoxy)phenoxy]ethoxy}-3-(1-piperazinyl)pyrazine,

[0175]2-{[3-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)phenoxy]methyl}-benzonitrile,

[0176]2-(1-piperazinyl)-3-{2-[3-(tetrahydro-2H-pyran-4-yloxy)phenoxy]ethoxy}-pyrazine,

[0177]N,N-Dimethyl-N-{2-[3-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-phenoxy]-ethyl}amine,

[0178]7-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-2H-chromen-2-one,

[0179]1-(3-{2-[(2-Chloro-3-pyridinyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine,particularly the (R)-enantiomer thereof,

[0180] 7-Isoquinolinyl 2-{[3-(1-piperazinyl)]-2-pyrazinyl}oxy)ethylether,

[0181] 2-(2-Chloro-4-methoxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether, 4-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-2-quinolinamine,

[0182] and their pharmacologically acceptable salts and solvates.

[0183] As mentioned above, the compounds of the present invention areuseful for the treatment (including prophylactic treatment) ofserotonin-related disorders, especially 5-HT2 receptor-related, in ahuman being or in an animal (including e.g, pets), such as eatingdisorders, especially obesity; memory disorders, such as Alzheimer'sdisease, schizophrenia; mood disorders, including, but not restrictedto, major depression and bipolar depression, including both mild andmanic bipolar disorder, seasonal affective disorder (SAD): anxietydisorders, including, situational anxiety, generalised anxiety disorder,primary anxiety disorders (panic disorders, phobias,obsessive-compulsive disorders, and post-traumatic stress disorders),and secondary anxiety disorders (for example anxiety associated withsubstance abuse); pain; sexual dysfunctions; and urinary disorders, suchas urinary incontinence.

[0184] The compounds of the present invention in labelled form, e.g,isotopically labelled, may be used as a diagnostic agent.

[0185] The compounds of the general formula (I) above may be preparedby, or in analogy with, conventional methods, and especially accordingto or in analogy with the following methods.

[0186] Method A:

[0187] Compounds of formula (I) above in which A is bound to Ar via anO, S or N atom in A, and (i) n=0 and R₁ is a saturated aminoazacyclic,aminodiazacyclic, diazacyclic or diazabicyclic residue, or (ii) n=1, Bis —N(R₆)— or —N(R₆)C(R₄)(R₅)—, wherein R₄, R₅ and R₆ are as definedabove, and R₁ is a saturated or unsaturated azacyclic, or a saturatedazabicyclic, residue, are prepared by reacting a compound of thestructural formula (III):

[0188] wherein Ar is as defined above and Hal is halogen, with acompound R-A′-X′-H or its corresponding anion where X′ is —O—, —S— or—N(R₁₅)-A′ is C₁₋₈-alkylene wherein the carbon chain may be interruptedby one or more heteroatoms and which malt have a terminal heteroatombinding to R., said heteroatoms being selected from N, O and S, and Rand R₁₅ are as defined above, to produce a compound of the formula (IV):

[0189] wherein Ar, X′, A′, R and Hal are as defined above. The compoundR-A′-X′-H may be converted completely or partially to its correspondinganion by treatment with bases, such as triethylamine,1,8-diazabicyclo[5.4.0]undec-7-ene, K₂CO₃, NaOH, NaH, KO-t-Bu, lithiumdiisopropylamide or the like. The reaction is carried out in a solvent,such as dioxane, tetrahydrofuran or N,N-dimethylformamide (DMF), at0-200° C. for 1-24 hours. The compound of formula (IV) is reacted with 1to 10 molar equivalents of the appropriate amine in a solvent, such asacetonitrile, dioxane, tetrahydrofuran, n-butanol, DMF, or in a mixtureof solvents such as DMF/dioxane, optionally in the presence of a base,such as K₂CO₃, Na₂CO₃, Cs₂CO₃, NaOH, triethylamine, pyridine or thelike, at 0-200° C. for 1-24 hours to produce the compound of formula(I).

[0190] Exemplary amines have the following structures:

[0191] wherein R₂₃, R₂₄, y and z are as defined above, and Z has themeanings defined for R₂₂ in formula (Ib) above or is a suitableprotecting group such as tert-butoxycarbonyl, trityl or benzyl.

[0192] Method B:

[0193] Compounds of formula (I) in which n=1, B is oxygen, sulphur andR₁ is a saturated azacyclic or azabicyclic residue, or a group—[C(R₄)(R₅)]_(x)N(R_(2a))(R_(3a)), wherein R₂, R₃, R₄, R₅ and x are asdefined above, are prepared by reacting a compound of formula (IV) abovewith a corresponding hydroxy- or mercapto-substituted azacyclic orazabicyclic compound, or with a compound HO—R₁ or HS—R₁, where R₁ is—[C(R₄)(R₅)]_(x)N(R_(2a))(R_(3a)). Exemplary hydroxy- andmercapto-substituted compounds have the following structures:

[0194] wherein Z is as defined above.

[0195] The reaction is carried out in a solvent, such as toluene, DMF ordioxane, in the presence of a base, such as1,8-diazabicyclo[5.4.0]undec-7-ene, KOH, KO-t-Bu, NaH or the like, at0-200° C. for 1-24 hours.

[0196] Method C:

[0197] Compounds of formula (I), wherein A is bound to R via an oxygenor sulphur atom in A, are prepared by reacting a compound of formula(V):

[0198] wherein Ar, R₁, B and n are as defined above, A″ is C₁₋₈-alkylenewherein the carbon chain may be interrupted by one or more heteroatomsand which may have a terminal heteroatom bound to Ar, said heteroatomsbeing selected from N, O and S, and L is a hydroxy, thiol or a leavinggroup such as, for example, halogen, tosyloxy, mesyloxy and the like,with a compound R—OH or R—SH, where R is as defined above, to producethe compound of formula (I).

[0199] When L is a free hydroxy or thiol group, the reaction may becarried out in the presence of diethyl azodicarboxylate (DEAD) or1,1′-azobis(N,N-dimethylformamide) (cf. Tetrahedron Lett. 1995, 36,3789-3792), preferably DEAD, and triphenylphosphine (PPh₃) in a solventsuch as tetrahydrofuran or dichloromethane (Mitsunobu reaction; see Org.React. 1992, 42, 335-656).

[0200] When L is a leaving group, the reaction may be carried out in thepresence of a suitable base, such as Na₂CO₃, K₂CO₃, Cs₂CO₃, KOH,triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene or the like, in asolvent, such as acetonitrile or DMF, at 0-200° C. for 1-24 hours.

[0201] In case the group -(B)_(n)R₁ in formula (V) contains a primary orsecondary amino group, the nitrogen may be protected with a suitableprotecting group, preferably tert-butoxycarbonyl, trityl or benzyl.N-Deprotection is then carried out by conventional methods such as thosedescribed in Protective Groups in Organic Synthesis, John Wiley & Sons,1991.

[0202] Method D:

[0203] Compounds of formula (I), in which A is bound to Ar via an O, Sor N atom in A, and wherein n=0, or n=1 and B is oxygen, nitrogen,sulphur, —N(R₆)C(R₄)(R₅)—, wherein R₄, R₅ and R₆ are as defined above,are prepared by reacting a compound of formula (III) above with anappropriate amine, or an appropriate hydroxy- or mercapto-substitutedcompound to produce a compound of formula (VI):

[0204] wherein Ar, B, R₁, Hal and n are as defined above. The reactionconditions may be those described for method's A and B above. Thecompound of formula (VI) is reacted with a compound R-A′-X′-H or itscorresponding anion, where X′ is —O—, —S— or —N(R₁₅)—, A′ isC₁₋₈-alkylene wherein the carbon chain may be interrupted by one or moreheteroatoms and which may have a terminal heteroatom binding to R, saidheteroatoms being selected from N, O and S, and R and R₁₅ are as definedabove, to produce a compound of the formula (I).

[0205] The reaction conditions may be those described for method Aabove.

[0206] Exemplary amines, hydroxy- and mercapto-substituted compoundsinclude those shown in connection with methods A and 13 above as well asa compound HO—R₁ or HS—R₁, where R₁ is—[C(R₄)(R₅)]_(x)N(R_(2a))(R_(3a)), and wherein R₂, R₃, R₄, R₅ and x areas defined above.

[0207] Compounds of formula (I), in which Ar represents an optionallysubstituted phenyl, naphthyl, pyridyl, or quinolinyl nucleus and (i) Ais oxygen or (ii) A is bound to Ar via an oxygen atom in A, may beprepared by methods well known in the art, as illustrated in Examples184 and 185 below.

[0208] An obtained compound of formula (I) may be converted to anothercompound of formula (I) by methods well known in the art (illustrated ine.g. Example 216).

[0209] The processes described above may be carried out to give acompound of the invention in the form of a free base or as an acidaddition salt. A pharmaceutically acceptable acid addition salt may beobtained by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds.Examples of addition salt forming acids are maleic acid, fumaric acid,succinic acid, methanesulfonic acid, trifluoroacetic acid, acetic acid,oxalic acid, benzoic acid, hydrochloric acid, sulphuric acid, phosphoricacid, and the like.

[0210] The compounds of formula (I) may possess one or more chiralcarbon atoms, and they may therefore be obtained in the form of opticalisomers, e.g, as a pure enantiomer, or as a mixture of enantiomers(racemate) or as a mixture containing diastereomers. The separation ofmixtures of optical isomers to obtain pure enantiomers is well known inthe art and may, for example, be achieved by fractional crystallizationof salts with optically active (chiral) acids or by chromatographicseparation on chiral columns.

[0211] The necessary starting materials for preparing the compounds offormula (I) are either known or may be prepared in analogy with thepreparation of known compounds. For example, the aryloxy- andheteroaryloxyethanols used in the preparation of the novel compounds offormula (I) may be prepared using the methods depicted in Scheme 1below.

[0212] In accordance with the present invention, the compounds offormula (I), in the form of free bases or salts with physiologicallyacceptable acids, can be brought into suitable galenic forms, such ascompositions for oral use, for injection, for nasal spray administrationor the like, in accordance with accepted pharmaceutical procedures. Suchpharmaceutical compositions according to the invention comprise aneffective amount of the compounds of formula (I) in association withcompatible pharmaceutically acceptable carrier materials, or diluents,as are well known in the art. The carriers may be any inert material,organic or inorganic, suitable for enteral, percutaneous, subcutaneousor parenteral administration, such as: water, gelatin, gum arabicum,lactose, microcrystalline cellulose, starch, sodium starch glycolate,calcium hydrogen phosphate, magnesium stearate, talcum, colloidalsilicon dioxide, and the like. Such compositions may also contain otherpharmacologically active agents, and conventional additives, such asstabilizers, wetting agents emulsifiers, flavouring agents, buffers, andthe like.

[0213] The compositions according to the invention can e.g, be made upin solid or liquid form for oral administration, such as tablets, pills,capsules, powders, syrups, elixirs, dispersable granules, cachets,suppositories and the like, in the form of sterile solutions,suspensions or emulsions for parenteral administration, sprays, e.g, anasal spray, transdermal preparations, e.g, patches, and the like.

[0214] As mentioned above, the compounds of the invention may be usedfor the treatment of serotonin-related disorders in a human being or ananimal, such as eating disorders, particularly obesity, memorydisorders, schizophrenia, mood disorders, anxiety disorders, pain,sexual dysfunctions, and urinary disorders. The compounds may also beuseful for treating gastrointestinal disorders, such as gastrointestinalmobility disorders, e.g, irritable bowel syndrome (IBS), or glaucoma.The dose level and frequency of dosage of the specific compound willvary depending on a variety of factors including the potency of thespecific compound employed, the metabolic stability and length of actionof that compound, the patient's age, body weight, general health, sex,diet, mode and time of administration, rate of excretion, drugcombination, the severity of the condition to be treated, and thepatient undergoing therapy. The daily dosage may, for example, rangefrom about 0.001 mg to about 100 mg per kilo of body weight,administered singly or multiply in doses, e.g, from about 0.01 mg toabout 25 mg each. Normally, such a dosage is given orally but parenteraladministration may also be chosen.

[0215] The invention will now be further illustrated by the followingnon-limiting Examples.

EXAMPLES

[0216] General:

[0217] The structures of the prepared compounds were confirmed bystandard spectroscopical methods, and elemental analysis and/or highresolution MS. The NMR data were obtained on a JEOL JNM-EX 270, a Bruker400 DPX or a Bruker DRX 50( ) spectrometer. IR spectra were obtained ona Perkin Elmer SPECTRUM 1000 FT-IR spectrometer. High resolution MS wereobtained on a Micromass LCT spectrometer. Elemental analysis wasperformed by Mikro Kemi AB. Uppsala, Sweden. Melting points, when given,ere obtained on a Büchi or a Gallenkamp melting point apparatus and areuncorrected.

Example 1

[0218] 2-(2-Phenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether, Maleate.

[0219] Step 1: 2-Chloro-3-(2-phenoxyethoxy)pyrazine.

[0220] NaO-t-Bu (2.91 g, 30.29 mmol) was added to a mixture of2,3-dichloropyrazine (4.75 g, 31.9 mmol) and 2-phenoxyethanol (4.18 g,30.3 mmol) in dioxane (25 mL). The reaction mixture was stirred atambient temperature for 1.5 h and then filtered. The filtrate wasconcentrated under reduced pressure and the crystalline residue obtainedwas dried in a vacuum oven affording 4.4 g (62%) of the title compoundas white waxy crystals: mp 55-54° C. Anal. (C₁₂H₁₁ClN₂O₂) C, H, N.

[0221] Step 2: 2-(2-Phenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether,Maleate.

[0222] A mixture of the product from Step 1 (1.705 g, 6.80 mmol),piperazine (1.75 g, 20.3 mmol), and K₂CO₃ (1.16 g, 8.39 mmol) inacetonitrile (10 mL) was stirred at 50° C. for 1.5 h and for a further 3h at 80° C. The reaction mixture was diluted with CH₂Cl₂, filtered, andconcentrated. Purification of the semi-solid residue by chromatographyon silica gel using CHCl₃/MeOH (9:1) as eluent gave a beige oil. Thismaterial was redissolved in ether/CHCl₃ (9:1), dried over K₂CO₃, andfiltered through a short (3 cm) plug of alumina. The filtrate wasconcentrated in vacuo to afford 1.33 g (65%) of the title compound asthe free base. The free base was converted to the maleate andrecrystallized from MeOH/ether: mp 155-157° C.; HRMS m/z calcd forC₁₆H₂₀N₄O₂ (M)⁺ 300.1586, found 300.1573. Anal. (C₁₆H₂₀N₄O₂.C₄H₄O₄) C,H, N.

Example 2

[0223] 2-(2-Furylmethoxy)-3-(1-piperazinyl)pyrazine, Maleate.

[0224] Step 1: 2-Chloro-3-(2-furylmethoxy)pyrazine.

[0225] The title compound was prepared according to the proceduredescribed in Example 1, Step 1, starting from 2-furanmethanol (4.18 g,42.7 mmol), 2,3-dichloropyrazine (2.05 g, 13.8 mmol) and KO-t-BuO (1.82g, 16.2 mmol). The product, which was obtained as a yellowish oil in 68%yield, was used directly in the next step.

[0226] Step 2: 2-(2-Furylmethoxy)-3-(1-piperazinyl)pyrazine, Maleate.

[0227] The title compound was prepared according to the proceduredescribed in Example 1, Step 2, starting from2-chloro-3-(2-furylmethoxy)pyrazine (1.47 g, 7.0 mmol): yield 0.62 g(34%) as the free base. A portion of the free base was converted to themaleate salt: mp 118-120° C.; HRMS m/z calcd for C₁₃H₁₆N₄O₂ (M)⁺260.1273, found 260.1270. Anal. (C₁₃H₁₆N₄O₂.C₄H₄O₄) C, H, N.

Example 3

[0228] 2-(2-Phenoxyethoxy)-3-(1-piperazinyl)quinoxaline, Hydrochloride.

[0229] Step 1: 2-Chloro-3-(2-phenoxyethoxy)quinoxaline.

[0230] The title compound was prepared according to the proceduredescribed in Example 1, Step 1, starting from 2-phenoxyethanol (3.7 g,26.8 mmol), 2,3-dichloroquinoxaline (1.33 g, 6.7 mmol) and KO-t-Bu (0.75g, 6.7 mmol): yield 0.74 g (37%); mp 99.5-101.5° C.; HRMS m/z calcd forC₁₆H₁₃ClN₂O₂ (M)⁺ 300.0666, found 300.0672. Anal. (C₁₆H₁₃ClN₂O₂) C, H,N.

[0231] Step 2: 2-(2-Phenoxyethoxy)-3-(1-piperazinyl)quinoxaline,Hydrochloride.

[0232] The title compound was prepared according to the proceduredescribed in Example 1, Step 2, starting from2-chloro-3-(2-phenoxyethoxy)quinoxaline (0.65 g. 2.15 mmol): yield 0.44g (58%) as the free base. A portion of the free base was converted toits hydrochloride salt: mp 123-126° C.; HRMS nm/z calcd for C₂₀H₂₂N₄O₂(M)⁺ 350.1743, found 350.1748. Anal. (C₂₀H₂₂N₄O₂.1.75 HCl 0.5H₂O) C, H,N.

Example 4

[0233] 2-[2-(2-Naphthyloxy)ethoxy]-3-(1-piperazinyl)pyrazine,Trifluoroacetate.

[0234] Step 1: 2-Chloro-3-[2-(2-naphthyloxy)ethoxy]pyrazine.

[0235] Sodium hydride (55% dispersion in mineral oil; 44 mg, 1.0 mmol)was added to a mixture of 2-(2-naphthoxy)ethanol (188 mg, 1.00 mmol) and2,3-dichloropyrazine (149 mg, 1.00 mmol) in dioxane (0.5 mL), and thereaction mixture was stirred at 400C for 15 h. The crude material wasused directly in Step 2.

[0236] Step 2: 2-[2-(2-Naphthyloxy)ethoxy]-3-(1-piperazinyl)pyrazine,Trifluoroacetate.

[0237] A solution of piperazine (430 mg, 5.00 mmol) in a mixture ofdioxane (0.5 mL) and DMF (1 mL) was added to the crude material fromStep 1. The reaction mixture was stirred at 60° C. for 15 h, thendiluted with EtOAc, washed with water, dried (MgSO₄), and concentratedunder reduced pressure. The residue was purified by chromatography onsilica gel using EtOAc/MeOH/HOAc/H₂O (20:3:3:2) as eluent. Theproduct-containing fractions were combined and concentrated. The residuewas further purified by C-18 HPLC using CH₃CN/H₂O/TFA (gradient: CH₃CN0% to 100%, TFA 0.1%) to give 34.5 mg (10%) of the title product. HRMSm/z calcd for C₂₀H₂₂N₄O₂ (M)⁺ 1350.1743, found 350.1742.

[0238] Examples 5-20 were prepared in an analogous manner starting from2,3-dichloropyrazine (1 mmol) and the appropriate alcohol (1 mmol).

Example 5

[0239] 2-(4-Bromophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether,Trifluoroacetate.

[0240] The title compound was prepared starting from2-(4-bromophenoxy)ethanol to give 47 mg (12%). HRMS m/z calcd forC₁₆H₁₉BrN₄O₂ (M)⁺ 378.0691, found 378.0698.

Example 6

[0241] 2-(2-Chlorophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether,Trifluoroacetate.

[0242] The title compound was prepared starting from2-(2-chlorophenoxy)ethanol to give 32 mg (10%). HRMS m/z calcd forC₁₆H₁₉ClN₄O₂ (M)⁺ 334.1197, found 334.1195.

Example 7

[0243] 2-(4-Chlorophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether,Trifluoroacetate.

[0244] The title compound was prepared starting from2-(4-chlorophenoxy)ethanol to give 56 mg (17%). HRMS m/z calcd forC₁₆H₁₉ClN₄O₂ (M)⁺ 334.1197, found 334.1182.

Example 8

[0245] 2-Phenoxypropyl 3-(1-piperazinyl)-2-pyrazinyl ether,Trifluoroacetate.

[0246] The title compound was prepared starting from 2-phenoxypropanolto give 24 mg (6%).

[0247] HRMS m/z calcd for C₁₇H₂₂N₄O₂ (M)⁺ 314.1743, found 314.1742.

Example 9

[0248] 2-Phenoxy-1-methylethyl 3-(1-piperazinyl)-2-pyrazinyl ether,Trifluoroacetate.

[0249] The title compound was prepared starting from1-phenoxy-2-propanol to give 29 mg (9%). HRMS m/z calcd for C₁₇H₂₂N₄O₂(M)⁺ 314.1743, found 314.1732.

Example 10

[0250] 2-(2-Methoxyphenoxy)-1-methylethyl 3-(1-piperazinyl)-2-pyrazinylether, Trifluoroacetate.

[0251] The title compound was prepared starting from1-(2-methoxyphenoxy)-2-propanol to give 25 mg (5%). HRMS m/z calcd forC₁₈H₂₄N₄O₃ (M)⁺ 344.1848, found 344.1852.

Example 11

[0252] 2-(3-Methoxyphenoxy)-1-methylethyl 3-(1-piperazinyl)-2-pyrazinylether, Trifluoroacetate.

[0253] The title compound was prepared starting from1-(3-methoxyphenoxy)-2-propanol to give 38 mg (11%). HRMS m/z calcd forC₁₈H₂₄N₄O₃ (M)⁺ 344.1848, found 344.1842.

Example 12

[0254] 2-(2-Methylphenoxy)-1-methylethyl 3-(1-piperazinyl)-2-pyrazinylether, Trifluoroacetate.

[0255] The title compound was prepared starting, from1-(2-methylphenoxy)-2-propanol to give 60 mg (18%). HRMS m/z calcd forC₁₈H₂₄N₄O₂ (M)⁺ 328.1899, found 328.1898.

Example 13

[0256] 2-(4-Methylphenoxy)-1-methylethyl 3-(1-piperazinyl)-2-pyrazinylether, Trifluoroacetate.

[0257] The title compound was prepared starting from1-(4-methylphenoxy)-2-propanol to give 12 mg (3%). HRMS m/z calcd forC₁₈H₂₄N₄O₂ (M)⁺ 328.1899, found 328.1896.

Example 14

[0258] 2-(Phenylthio)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether,Trifluoroacetate.

[0259] The title compound was prepared starting from2-(phenylthio)ethanol to give 30 mg (10%). HRMS m/z calcd for C₁₆H₂₀N₄OS(M)⁺ 316.1358, found 316.1359.

Example 15

[0260] 2-(Anilino)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether,Trifluoroacetate.

[0261] The title compound was prepared starting from 2-aminoethanol togive 48 mg (16%).

[0262] HRMS m/z calcd for C₁₆H₂₁N₅O (M)⁺ 299.1746, found 299.1754.

Example 16

[0263] 2-(N-Ethylanilino)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether,Trifluoroacetate.

[0264] The title compound was prepared starting from2-(N-ethylanilino)ethanol to give 7 mg (2%). HRMS m/z calcd forC₁₈H₂₅N₅O (M)⁺ 327.2059, found 327.2057.

Example 17

[0265] 2,3-Dihydro-1,4-benzodioxin-2-ylmethyl3-(1-piperazinyl)-2-pyrazinyl ether, Trifluoroacetate.

[0266] The title compound was prepared starting from2-hydroxymethyl-1,4-benzodioxane to give 22 mg (5%). HRMS m/z calcd forC₁₇H₂₀N₄O₃ (M)⁺ 328.1535, found 328.1519.

Example 18

[0267] 3-Phenylpropyl 3-(1-piperazinyl)-2-p1), azinyl ether,Trifluoroacetate.

[0268] The title compound was prepared starting from 3-phenyl-1-propanolto give 9 mg (2%). HRMS m/z calcd for C₁₇H₂₁N₄O (M)⁺ 298.1794, found298.1795.

Example 19

[0269] 4-Phenylbutyl 3-(1-piperazinyl)-2-pyrazinyl ether,Trifluoroacetate.

[0270] The title compound was prepared starting from 4-phenyl-1-butanolto give 10 mg (2%).

[0271] HRMS m/z calcd for C₁₈H₂₄N₄O (M)⁺ 312.1950, found 312.1963.

Example 20

[0272] 2-(Benzyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether,Trifluoroacetate.

[0273] The title compound was prepared starting from 2-benzyloxyethanolto give 31 mg (7%).

[0274] HRMS m/z calcd for C₁₇H₂₂N₄O₂ (M)⁺ 314.1743, found 314.1739.

Example 21

[0275]4-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-1,3-benzoxazol-2-amine,Fumarate.

[0276] Step 1: 4-(2-Hydroxyethoxy)-2-amino-1,3-benzoxazol.

[0277] The title compound was prepared according to the procedure ofExample 91, Step 1, starting from 4-hydroxy-2-amino-1.3-benzoxazol*(0.97 g, 6.5 mmol) and ethylene carbonate (0.63 g, 7.1 mmol). Solid;yield 46%; mp 124-126° C. Anal. (C₉H₁₀N₂O₃) C, H, N.

[0278] Step 2:4-{2-[(3-Chloro-2-pyrazinyl)oxy]ethoxy}-1,3-benzoxazol-2-amine.

[0279] The title compound was prepared according to the procedure ofExample 4, Step 1, except that 4 equiv of both NaH and2.3-dichloropyrazine were used, starting from the product of Step 1. Thereaction temperature was 90° C. The crude product was used directly inthe next step.

[0280] Step 3:4-(2-{[3-(1-Piperazinyl)-2-pyrazinyl)oxy]ethoxy}-1,3-benzoxazol-2-amine.Fumarate.

[0281] The title compound was prepared according to the procedure ofExample 1. Step 2, starting from the product of Step 2 above. Yield offree base 24%. The free base was converted to the fumarate salt: mp138-140° C. Anal. (C₁₇H₂₀N₆O₃ C₄H₄O₄.0.25H₂O)C, H, N.

Example 22

[0282] 2-(Phenoxy)ethyl 3-(3-amino-1-pyrrolidinyl)-2-pyrazinyl ether.

[0283] The title compound was prepared according to the proceduredescribed in Example 4, Step 2, starting from2-chloro-3-(2-phenoxyethoxy)pyrazine (150 mg, 0.60 mmol; from Example 1,Step 1) and 3-aminopyrrolidine (270 mg, 3.13 mmol) with the exceptionthat a final extraction step between EtOAc and 5% aqueous NaOH wascarried out. This gave 121 mg (67%) of the title product. Anal.(C₁₆H₁₉N₄O₂) C, H; N: calcd, 18.65; found, 18.0.

Example 23

[0284] 2-(2-Chlorophenoxy)ethyl 3-(3-amino-1-pyrrolidinyl)-2-pyrazinylether.

[0285] The title compound was prepared according to the proceduredescribed in Example 4, Step 2, starting from2-chloro-3-[2-(2-chlorophenoxy)ethoxy]pyrazine* (150 mg, 0.53 mmol) and3-aminopyrrolidine (252 mg, 2.92 mmol) with the exception that a finalextraction step between EtOAc and 5% aqueous NaOH was carried out. Thisgave 100 mg (56%) of the title product. Anal. (C₁₆H₁₉ClN₄O₂) C, H; N:calcd, 16.73; found, 16.0.

Example 24

[0286] 2-(4-Chlorophenoxy)ethyl 3-(3-amino-1-pyrrolidinyl)-2-pyrazinylether.

[0287] The title compound was prepared according to the proceduredescribed in Example 4, Step 2, starting from2-chloro-3-[2-(4-chlorophenoxy)ethox;]pyrazine* (150 mg, 0.53 mmol) and3-aminopyrrolidine (247 ml. 2.87 mmol) with the exception that a finalextraction step between EtOAc and 5% aqueous NaOH was carried out. Thisgave 123 mg (69%) of the title product. Anal. (C₁₆H₁₉Cl N₄O₂) H, N; C:calcd. 57.40; found, 56.9.

Example 25

[0288] 2-(Phenoxy)ethyl 3-(1,4-diazepan-1-yl)-2-pyrazinyl ether.

[0289] The title compound was prepared according to the proceduredescribed in Example 4, Step 2, starting from2-chloro-3-(2-phenoxyethoxy)pyrazine (150 mg, 0.60 mmol; from Example 1,Step 1) and homopiperazine (250 mg, 2.5 mmol) with the exception that afinal extraction step between EtOAc and 5% aqueous NaOH was carried out.This gave 141 mg (75%) of the title product. Anal.(C₁₇H₂₂N₄O₂.0.35EtOAc) C, H, N.

Example 26

[0290] 2,3-Dihydro-1,4-benzodioxin-2-ylmethyl3-(1,4-diazepan-1-yl)-2-pyrazinyl ether.

[0291] The title compound was prepared according to the proceduredescribed in Example 4, Step 2, starting from2-chloro-3-(2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)pyrazine* (150 mg,0.54 mmol) and homopiperazine (266 mg, 2.66 mmol) with the exceptionthat a final extraction step between EtOAc and 5% aqueous NaOH wascarried out. This gave 105 mg (57%) of the title product. Anal.(C₁₈H₂₄N₄O₃) H, N; C: calcd, 63.14; found, 62.70.

Example 27

[0292] 2-(4-Chlorophenoxy)ethyl 3-(1,4-diazepan-1-yl)-2-pyrazinyl ether.

[0293] The title compound was prepared according to the proceduredescribed in Example 4, Step 2, starting from2-chloro-3-[2-(4-chlorophenoxy)ethoxy]pyrazine* (150 mg, 0.53 mmol) andhomopiperazine (287 mg, 2.87 mmol) with the exception that a finalextraction step between EtOAc and 5% aqueous NaOH was carried out. Thisgave 128 mg (69%) of the title product. HRMS m/z calcd for C₁₇H₂₁ClN₄O₂(M)⁺ 348.1353, found 348.1353. Anal. (C₁₇H₂₁ClN₄O₂) C, H, N.

Example 28

[0294] 2-(Phenoxy)ethyl 3-(3-methyl-1-piperazinyl)-2-pyrazinyl ether.

[0295] The title compound was prepared according to the proceduredescribed in Example 4. Step 2, starting from2-chloro-3-(2-phenoxyethoxy)pyrazine (150 mg, 0.54 mmol; from Example 1,Step 1) and 2-methylpiperazine (250 mg, 2.5 mmol) with the exceptionthat a final extraction step between EtOAc and 5% aqueous NaOH wascarried out. This gave 138 mg (73%) of the title product. Anal.(C₁₇H₂₂N₄O₂) C, H, N.

Example 29

[0296] 2-(4-Chlorophenoxy)ethyl 3-(3-methyl-1-piperazinyl)-2-pyrazinylether.

[0297] The title compound was prepared according to the proceduredescribed in Example 4, Step 2, starting from2-chloro-3-[2-(4-chlorophenoxy)ethoxy]pyrazine* (150 mg, 0.53 mmol) and2-methylpiperazine (256 mg, 2.56 mmol) with the exception that a finalextraction step between EtOAc and 5% aqueous NaOH was carried out. Thisgave 143 mg (77%) of the title product. HRMS m/z calcd for C₁₇H₂₁ClN₄O₂(M)⁺ 348.1353, found 348.1370. Anal. (C₁₇H₂₁ClN₄O₂) C, H, N.

Example 30

[0298] 2-(2-Methoxyphenoxy)-1-methylethyl3-(3-methyl-1-piperazinyl)-2-pyrazinyl ether.

[0299] The title compound was prepared according to the proceduredescribed in Example 4. Step 2, starting from2-chloro-3-[2-(2-methoxyphenoxy)-1-methylethoxy]pyrazine* (150 mg, 0.51mmol) and 2-methylpiperazine (260 mg, 2.6 mmol) with the exception thata final extraction step between EtOAc and 5% aqueous NaOH was carriedout. This gave 118 mg (65%) of the title product. HRMS m/z calcd forC₁₉H₂₆N₄O₃ (I)+358.2005, found 358.2018. Anal. (C₁₉H₂₆N₄O₃) C, H, N.

Example 31

[0300] 2,3-Dihydro-1,4-benzodioxin-2-ylmethyl3-(3-methyl-1-piperazinyl)-2-pyrazinyl ether.

[0301] The title compound was prepared according to the proceduredescribed in Example 4, Step 2, starting from2-chloro-3-(2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)pyrazine* (150 mg,0.54 mmol) and 2-methylpiperazine (293 mg, 2.92 mmol) with the exceptionthat a final extraction step between EtOAc and 5% aqueous NaOH wascarried out. This gave 118 mg (64%) of the title product. HRMS m/z calcdfor C₁₈H₂₂N₄O₃ (M)⁺ 342.1692, found 342.1678. Anal. (C₁₈H₂₂N₄O₃) H, N;C: calcd, 63.14; found, 62.30.

Example 32

[0302] 2-(Phenoxy)ethyl 3-(4-ethyl-1-piperazinyl)-2-pyrazinyl ether.

[0303] The title compound was prepared according to the proceduredescribed in Example 4, Step 2, starting from2-chloro-3-(2-phenoxyethoxy)pyrazine (150 mg, 0.60 mmol; from Example 1,Step 1) and N-ethylpiperazine (250 mg, 2.19 mmol) with the exceptionthat a final extraction step between EtOAc and 5% aqueous NaOH wascarried out. This gave 127 mg (64%) of the title product. Anal.(C₁₈H₂₄N₄O₂) C, H, N.

Example 33

[0304] 2-(2-Chlorophenoxy)ethyl 3-(4-ethyl 1-piperazinyl)-2-pyrazinylether.

[0305] The title compound was prepared in an analogous manner to Example4, Step 2, starting from 2-chloro-3-[2-(2-chlorophenoxy)ethoxy]pyrazine*(150 mg, 0.53 mmol) and N-ethylpiperazine (221 mg, 1.93 mmol) with theexception that a final extraction step between EtOAc and 5% aqueous NaOHwas carried out. This gave 100 mg (52%) of the title product. Anal.(C₁₈H₂₄C₁₄O₂) C, H, N.

Example 34

[0306] 2-(4-Chlorophenoxy)ethyl 3-(4-ethyl-1-piperazinyl)-2-pyrazinylether.

[0307] The title compound was prepared according to the proceduredescribed in Example 4. Step 2, starting from2-chloro-3-[2-(4-chlorophenoxy)ethoxy]pyrazine* (150 mg, 0.53 mmol) andN-ethylpiperazine (221 mg, 1.93 mmol) with the exception that a finalextraction step between EtOAc and 5% aqueous NaOH was carried out. Thisgave 138 mg (72%) of the title product. HRMS m/z calcd for C₁₈H₂₃ClN₄O₂(M)⁺ 362.1510, found 362.1526. Anal. (C₁₈H₂₃ClN₄O₂).C, H, N.

Example 35

[0308] 2,3-Dihydro-1,4-benzodioxin-2-ylmethyl3-(4-ethyl-1-piperazinyl)-2-pyrazinyl ether.

[0309] The title compound was prepared according to the proceduredescribed in Example 4, Step 2, starting from2-chloro-3-(2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)pyrazine* (150 mg,0.54 mmol) and N-ethylpiperazine (219 mg, 1.92 mmol) with the exceptionthat a final extraction step between EtOAc and 5% aqueous NaOH wascarried out. This gave 128 mg (66%) of the title product. HRMS m/z calcdfor C₁₉H₂₄N₄O₃ (M)+356.1848, found 356.1848. Anal. (C₁₉H₂₄N₄O₃) C, H, N.

Example 36

[0310] 2-(2-Methoxyphenoxy)-1-methylethyl3-(4-ethyl-1-piperazinyl)-2-pyrazinyl ether.

[0311] The title compound was prepared according to the proceduredescribed in Example 4, Step 2, starting from2-chloro-3-[2-(2-methoxyphenoxy)-1-methylethoxy]pyrazine* (150 mg, 0.51mmol) and N-ethylpiperazine (222 mg, 1.94 mmol) with the exception thata final extraction step between EtOAc and 5% aqueous NaOH was carriedout. This gave 127 mg (67%) of the title product. HRMS m/z calcd forC₂₀H₂₈N₄O₃ (M)+372.2161, found 372.2174. Anal. (C₂₀H₂₈N₄O₃) C, H, N.

Example 37

[0312] 2-(3-Bromophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether.

[0313] Step 1: 2-(3-Bromophenoxy)ethyl 3-chloro-2-pyrazinyl ether.

[0314] A mixture of 3-bromophenol (1.73 g. 10.0 mmol), ethylene oxide(0.44 g, 10 mmol). Et₃N (3 drops) and dioxane (4 mL) was heated at 100°C. in a sealed tube for 2 d. The solution was cooled in an ice-bath andKO-t-Bu (1.07 g, 9.50 mmol) followed by 2,3-dichloropyrazine (1.34 g, 9mmol) were added along with dioxane (1 mL). The mixture was stirred atroom temperature for 90 min, diluted with CH₂Cl₂ and filtered. Thefiltrate was concentrated and the residue was purified by chromatographyon silica gel (gradient: isohexane to 25% EtOAc/isohexane) to give 2.21g (75%) of the title product as a white solid: mp 57-58° C. Anal.(C₁₂H₁₀BrClN₂O₂) C, H, N.

[0315] Step 2: 2-(3-Bromophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether.

[0316] Piperazine (1.29 g, 15.0 mmol) and K₂CO₃ (0.69 g, 5.0 mmol) wereadded to a solution of 2-(3-bromophenoxy)ethyl 3-chloro-2-pyrazinylether (1.65 g, 5.00 mmol) in acetonitrile (25 mL) at room temperature.The mixture was heated at reflux for 21 h, allowed to cool, concentratedand the residue was partitioned between water and EtOAc. The layers wereseparated and the organic phase was washed with water and brine, anddried over MgSO₄. Purification by chromatography on silica gel(gradient: PhMe to PhMe/MeOH/Et₃N, 8:1:1) gave 1.61 g (85%) of the titlecompound as a pale yellow oil that slowly solidified on standing: mp62-63° C. Anal. (C₁₆H₁₉BrN₄O₂) C, H, N.

Example 38

[0317] 2-[2-(2-Chlorophenoxy)ethoxy]-3-(1-piperazinyl)quinoxaline.

[0318] Step 1: 2-Chloro-3-[2-(2-chlorophenoxy)ethoxy]quinoxaline.2-(2-Chlorophenoxy)ethanol (0.229 g, 1.33 mmol) was treated with NaH(55% dispersion in mineral oil; 0.058 g, 1.33 mmol) in dioxane (2 mL).After stirring at room temperature for 3 h, the mixture was addeddropwise to a slurry of 2.3-dichloroquinoxaline (0.320 g, 1.60 mmol) indioxane (1 mL). The resulting mixture was stirred at room temperaturefor 15 h to produce the intermediate2-chloro-3-[2-(2-chlorophenoxy)ethoxy]quinoxaline which was useddirectly in the next step.

[0319] Step 2:2-[2-(2-Chlorophenoxy)ethoxy]-3-(1-piperazinyl)quinoxaline.

[0320] Piperazine (0.580 g. 6.65 mmol) was added to the crude materialfrom Step 1 and the resulting mixture was stirred at room temperaturefor 5 h. The solvent was evaporated, and the crude mixture was dissolvedin DMSO and precipitated with water. The precipitate was purified bychromatography on silica gel using EtOAc/HOAc/MeOH/H₂O (40:3:3:2) aseluent to afford 0.100 g (22%) of the title compound as a yellow oil.HRMS m/z calcd for C₂₀H₂₁ClN₄O₂ (M)⁺ 384.1353, found 384.1334.

[0321] Examples 39-45 were prepared according to the procedure ofExample 38, starting from 2,3-dichloroquinoxaline and the appropriatealcohol.

Example 39

[0322] 2-[2-(4-Chlorophenoxy)ethoxy]-3-(1-piperazinyl)quinoxaline.

[0323] The title compound was prepared starting from2-(4-chlorophenoxy)ethanol (0.229 g, 1.33 mmol) to give 0.250 g (56%) ofa yellow solid: mp 108-112° C.; HRMS m/z calcd for C₂₀H₂₁ClN₄O₂ (M)⁺384.1353, found 384.1347.

Example 40

[0324] 2-[2-(Phenylthio)ethoxy]-3-(1-piperazinyl)quinoxaline.

[0325] The title compound was prepared starting from2-(phenylthio)ethanol (0.205 g, 1.33 mmol) to give 0.045 g (9%) of ayellow oil. HRMS m/z calcd for C₂₀H₂₂N₄OS (M)⁺ 366.1514, found 366.1509.

Example 41

[0326] 2-(1-Methyl-2-phenoxyethoxy)-3-(1-piperazinyl)quinoxaline.

[0327] The title compound was prepared starting from1-methyl-2-phenoxyethanol (0.202 g, 11.33 mmol) to give 0.084 g (17%) ofa yellow oil. HRMS m/z calcd for C₂₁H₂₄N₄O₂ (M)⁺ 364.1899, found364.1908.

Example 42

[0328]2-[1-Methyl-2-(4-methylphenoxy)ethoxy]-3-(1-piperazinyl)quinoxaline.

[0329] The title compound vas prepared starting from1-methyl-2-(4-methylphenoxy)ethanol (0.221 g, 1.33 mmol) to give 0.047 g(9%) of a yellow oil. Anal. (C₂₂₁H₂₆N₄O₂) C, H, N.

Example 43

[0330]2-[2-(2-Methoxyphenoxy)-1-methylethoxy]-3-(1-piperazinyl)quinoxaline.

[0331] The title compound was prepared starting from1-methyl-2-(2-methoxyphenoxy)ethanol (0.242 g, 1.33 mmol) to give 0.072g (14%) of a yellow oil. Anal. (C₂₂H₂₆N₄O₃) C, H, N: calcd, 14.20;found, 13.70.

Example 44

[0332]2-(2,3-Dihydro-1,4-benzodioxin-2-ylmethoxy)-3-(1-piperazinyl)quinoxaline.

[0333] The title compound was prepared starting from2,3-dihydro-1,4-benzodioxin-2-ylmethanol (0.221 g, 1.33 mmol) to give0.18 g (35%) of a yellow oil. Anal. (C₂₁H₂₂N₄O₃) C, H, N.

Example 45

[0334] 2-[2-(2-Naphthyloxy)ethoxy]-3-(1-piperazinyl)quinoxaline.

[0335] The title compound was prepared starting from2-(2-naphthyloxy)ethanol (0.250 g, 1.33 mmol) to give 0.22 g (41%) of ayellow solid. HRMS m/z calcd for C₂₄H₂₄N₄O₂ (M)⁺ 400.1899, found400.1902.

Example 46

[0336] 2-(2-Phenoxyethylamino)-3-(1-piperazinyl)pyrazine.

[0337] Step 1: 2-Chloro-3-(2-phenoxyethylamino)pyrazine.

[0338] A mixture of 2-phenoxyethylamine (2.65 g, 19.3 mmol),2,3-dichloropyrazine (2.88 g, 19.3 mmol) and K₂CO₃ (2.67 g, 19.3 mmol)in acetonitrile (8 mL) was stirred in a sealed tube for 12 h at roomtemperature, and for a further 9.5 h at 80° C. The reaction mixture wasdiluted with ether, filtered, and concentrated. The residue was purifiedby chromatography on silica gel using n-hexane/EtOAc (7:3) as eluent togive 2.36 g (49%) of the title compound as a yellowish oil thatsolidified on standing: mp 51-53° C.;

[0339] HRMS m/z calcd for C₁₂H₁₂ClN₃O (M)⁺ 249.0669, found 249.0659.,Anal. (C₁₂H₁₂ClN₃O) C, H, N.

[0340] Step 2: 2-(2-Phenoxyethylamino)-3-(1-piperazinyl)pyrazine.

[0341] A mixture of the product from Step 1 above (1.59 g, 6.37 mmol),piperazine (1.56 g, 18.2 mmol), and K₂CO₃ (0.88 g, 6.4 mmol) inacetonitrile (10 mL) was stirred at 140° C. for 12 h in a sealed tube.After cooling, the reaction mixture was diluted with CH₂Cl₂, filtered,and concentrated. The semisolid residue was purified by chromatographyon silica gel using CHCl₃/MeOH (9:1) as eluent to give a beige oil. Thisoil was redissolved in CHCl₃, and filtered through a short (3 cm) plugof alumina covered with K₂CO₃. The pad was washed with several portions,of CHCl₃ and the resulting filtrate was concentrated to afford 1.48 g(78%) of the title product as a pale yellow oil. HRMS m/z calcd forC₁₆H₂₁N₅O (M)⁺ 299.1746, found 299.1753. Anal. (C₁₆H₂₁N₅O.1/3H₂O) C, H,N.

Example 47

[0342] N-Methyl-N-(2-phenoxyethyl)-3-(1-piperazinyl)-2-pyrazinamine,Fumarate.

[0343] Step 1: 3-Chloro-N-methyl-N-(2-phenoxyethyl)-2-pyrazinamine.

[0344] A mixture of 2,3-dichloropyrazine (6.64 g, 44.6 mmol) andN-methyl-N-(2-phenoxyethyl)amine* (4.5 g, 29.8 mmol) in DMF (5 mL) wasplaced in a sealed Pyrex tube and heated in a microwave oven (LabwellMW10) for 1×2 min followed by 2×1 min at 75W. The mixture wasconcentrated and the resulting oil was purified by column chromatographyon silica using hexane/EtOAc (95:5 followed by 93:7) to give 5.56 g(71%) of the title product as a colorless oil. HRMS m/z calcd forC₁₃H₁₄ClN₃O (M)⁺ 263.0825, found 263.0824.

[0345] Step 2:N-Methyl-N-(2-phenoxyethyl)-3-(1-piperazinyl)-2-pyrazinamine, Fumarate.

[0346] A mixture of the product obtained in Step 1 (5.0 g, 19 mmol) andpiperazine (5.0 g, 59.4 mmol) in DMF (10 mL) was placed in a sealedPyrex tube and heated in a microwave oven (Labwell MW10) for 2.5 min at75 W. The mixture was concentrated and the remaining yellower oil waspartitioned between water and CHCl₃. The water phase as extracted withCHCl₃ (×2) and the combined organic phases were extracted with 0.5 Maqueous HCl (×2). The combined aqueous phases were made alkaline (11MNaOH) and extracted with CHCl₃ (×3). The combined organic phases werewashed with water and brine, dried (MgSO₄), and concentrated to give thefree base of the title product as a light yellow oil. The free base wasconverted to its fumarate salt. Yield 1.38 g (17%) of off-white crystalsfrom methanol; mp 154° C. Anal. (C₁₇H₂₃N₅O C₄H₄O₄) H, N; C: calcd, 58.7;found, 58.05.

Example 48

[0347] 2-(Phenoxy)ethyl 3-(3-pyrrolidinyloxy)-2-pyrazinyl ether.

[0348] 2-Chloro-3-(2-phenoxyethoxy)pyrazine (150 mg, 0.60 mmol; fromExample 1, Step 1) was added to a stirred mixture of 3-pyrrolidinol (260mg, 2.99 mmol) and NaH (55% dispersion in mineral oil; 110 mg, 2.50mmol) in dioxane (2 mL), and the reaction was stirred at roomtemperature for 2 h. EtOAc was added and the mixture was washed withwater, dried (MgSO₄), and concentrated. The residue was purified bychromatography on silica gel using EtOAc/MeOH/HOAc/H₂O (50:40:9:1) aseluent to give 38 mg (22%) of the title compound. Anal. (C₁₆H₁₉N₃O₃) H;C: calcd, 63.77; found, 62.20; N: calcd, 13.94; found, 13.0.

Example 49

[0349] 2-(Phenoxy)ethyl 3-[(3R)-pyrrolidinyloxy]-2-pyrazinyl ether.

[0350] Step 1: 2-(Phenoxy)ethyl 3-[N-tert-butoxycarbonyl(3R)-pyrrolidinyloxy]-2-pyrazinyl ether.2-Chloro-3-(2-phenoxyethoxy)pyrazine (250 mg, 1.00 mmol; from Example 1,Step 1) was added to a mixture of N-Boc-(R)-3-pyrrolidinol (225 mg, 1.20mmol) and KO-t-Bu (140 mg, 1.25 mmol) in toluene (5 mL)), and thereaction was stirred at 95° C. for 30 min. The reaction mixture wasdiluted with toluene, washed with water, dried (MgSO₄), and concentratedunder reduced pressure. The residue was purified by chromatography onsilica gel using toluene/EtOAc (9:1) as eluent to give 261 mg (65%) ofthe title product which was used in the next step without furthercharacterization.

[0351] Step 2: 2-(Phenoxy)ethyl 3-[(3R)-pyrrolidinyloxxy]-2-pyrazinylether.

[0352] The product from Step 1 above was treated withCH₂Cl₂/trifluoroacetic acid/H₂O (50:45:5; 4 mL) for 30 min. The mixturewas concentrated and the residue was partitioned between 5% aqueous NaOHand CH₂Cl₂. After separation, the organic layer was dried (MgSO₄) andconcentrated. The residue was purified by chromatography on silica gelusing CH₂Cl₂/MeOH (8:2) as eluent to give 44 mg (15%) of the titleproduct: [α]_(D)=−4.6° (c 0.017, MeOH); HRMS m/z calcd for C₁₆H₁₉N₃O₃(M)⁺ 301.1426, found 301.1427.

Example 50

[0353] 2-(Phenoxy)ethyl 3-(4-piperidinyloxy)-2-pyrazinyl ether.

[0354] The title compound was prepared according to the proceduredescribed in Example 49 starting from2-chloro-3-(2-phenoxyethoxy)pyrazine (250 mg, 1.00 mmol; from Example 1,Step 1) and N-Boc-4-hydroxypiperidine (234 mg, 1.16 mmol) to give 112 mg(350% o) of the title product. HRMS m/z calcd for C₁₇H₂₃N₃O₃ (M)⁺315.1583, found 315.1570.

Example 51

[0355] 2-(Phenoxy)ethyl 3-[(2S)-pyrrolidinylmethoxy]-2-pyrazinyl ether.

[0356] The title compound was prepared according to the proceduredescribed in Example 49, starting from2-chloro-3-(2-phenoxyethoxy)pyrazine (250 mg, 1.00 mmol; from Example 1,Step 1) and N-Boc-L-prolinol (250 mg, 1.24 mmol). The intermediateproduct 2-(phenoxy)ethyl 3-[N-tert-butoxycarbonyl(2S)-pyrrolidinylmethoxy]-2-pyrazinyl ether was not characterized. Yield23 mg (7%); [a]D=13.2° (c 0.016, MeOH). HRMS m/z calcd for C₁₇H₂₁N₃O₃(M)⁺ 315.1583, found 315.1598.

Example 52

[0357] 2-(2-Methoxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether.

[0358] Step 1: 2-Chloro-3-(4-tert-butoxycarbonyl-1-piperazinyl)pyrazine.

[0359] A mixture of N-Boc-piperazine (11.47 g, 61.5 mmol), K₂CO₃ (8.5 g,61 mmol) and 2,3-dichloropyrazine (9.20 g, 61.7 mmol) in acetonitrile(100 mL) was stirred at 1000C for 40 h. The reaction mixture wasconcentrated, dissolved in toluene washed with water, dried (MgSO₄), andconcentrated. The residue was purified by chromatography on silica gelusing toluene/EtOAc (7:3) as eluent to give 18.3 g (100%) of the titleproduct. HRMS m/z calcd for C₁₃H₁₉N₄O₂ (M)⁺ 298.1197, found 298.1206.

[0360] Step 2:2-[3-(4-tert-Butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol.

[0361] KO-t-Bu (9.92 g, 103 mmol) was added to a mixture of the productobtained in Step 1 (18.14 g, 60.7 mmol) and ethylene glycol (25 mL, 448mmol) in pyridine (125 mL) at 85° C. The reaction mixture was stirredfor 15 h and then poured into ice-water and extracted with toluene. Theorganic phase was dried (MgSO₄) and concentrated. The residue waspurified by chromatography on silica gel using toluene/EtOAc (1:1) aseluent to give 16.9 g (85%) of the title product. HRMS m/z calcd forC₁₅H₂₄N₄O₄ (M)+324.1798, found 324.1784.

[0362] Step 3: 2-(2-Methoxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether.

[0363] 1,1′-Azobis(N,N-dimethylformamide) (TMAD; 60 mg, 0.35 mmol) wasdissolved in THF (1 mL) and DMF (0.5 mL) and added to a stirred solutionof the product from Step 2 (100 mg, 0.31 mmol), 2-methoxyphenol (124 mg,1.00 mmol) and triphenylphosphine (92 mg, 0.35 mmol) in THF (1 mL). Thereaction mixture was stirred for 15 h and then concentrated underreduced pressure. The residue was passed through a bed of silica gelusing toluene/EtOAc/MeOH (45:45:10) as eluent, and the pure fractionswere combined, concentrated and treated with CH₂Cl₂/TFA/H₂O (50:45:5; 5mL) for 30 min. The mixture was concentrated and the residue waspurified by chromatography oil silica gel using EtOAc/HOAc/MeOH/H₂O(20:3:3:2) as eluent. The combined product-containing fractions wereconcentrated and partitioned between 5% aqueous NaOH and CH₂Cl₂. Theorganic phase was concentrated, and the residue was purified bychromatography on silica gel using CH₂Cl/MeOH (8:2) as eluent to give1112 ma (11%) of the title product. HRMS m/z calcd for C₁₇ i),₂N₄O, (M)330.1692, found 330.1707.

[0364] Examples 53-68 were prepared according to the procedure describedin Example 52, Step 3, starting from2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol andthe requisite phenolic compound (1 mmol unless otherwise noted).

Example 53

[0365] 2-(4-n-Butoxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether,Trifluoroacetate.

[0366] The title compound was prepared starting from p-butoxyphenol, butno extraction with NaOH and without the third chromatographic step, togive 92 mg (19%) as the trifluoroacetate salt. HRMS m/z calcd forC₂₀H₂₈N₄O₃ (M)⁺ 372.2161, found 372.2162.

Example 54

[0367] 2-(2-Isopropoxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether.

[0368] The title compound was prepared starting from 2-isopropoxyphenolto give 216 mg (60%). HRMS m/z calcd for C₁₉H₂₆N₄O₃ (M)⁺ 358.2005, found358.2006.

Example 55

[0369] 2-(1-Naphthyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether.

[0370] The title compound was prepared starting from 1-naphthol to give142 mg (40%). HRMS m/z calcd for C₂₀H₂₂N₄O₂ (M)⁺ 350.1743, found350.1758.

Example 56

[0371] 2-(2,5-Difluorophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether,Trifluoroacetate.

[0372] The title compound was prepared starting from 2,5-difluorophenol,but no extraction with NaOH and without the third chromatographic step,to give 21 mg (6%) as the trifluoroacetate salt. HRMS m/z calcd forC₁₆H₁₈F₂N₄O(M)⁺ 336.1398. Found 336.1407.

Example 57

[0373] 2-(3,5-Dimethoxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether.

[0374] The title compound was prepared starting from 3,5-dimethoxyphenolto give 52 mg (14%). HRMS m/z calcd for C₁₈H₂₄N₄O₄ (M)⁺ 360.1798, found360.1808.

Example 58

[0375] 2-[2-(2-Methoxy-5-nitrophenoxy)ethoxy]-3-(1-piperazinyl)pyrazine,Hydrochloride.

[0376] The title compound was prepared starting from2-methoxy-5-nitrophenol (0.524 g, 3.08 mmol) to give 0.53 g (42%).Pos-EI-MS shows M and 10 ions supporting the stated structure. HRMS m/zcalcd for C₁₇H₂₁N₅O₅ (M)⁺ 375.1543, found 375.1561. Anal.(C₁₇H₂₁N₅O₅.0.5 HCl.1.3H₂O)C, H, N.

Example 59

[0377] 2-(2,6-Dimethoxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether, Trifluoroacetate

[0378] The title compound was prepared starting from 2,6-dimethoxyphenolto give 142 mg (30%). HRMS m/z calcd for C₁₈H₂₄N₄O₄ (M)⁺ 360.1798, found360.1797.

Example 60

[0379] 2-(2,3-Dimethoxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether

[0380] The title compound was prepared starting from 2,3-dimethoxyphenolto give 110 mg (31%). HRMS m/z calcd for C₁₈H₂₄N₄O₄ (M)⁺ 360.1798, found360.1800.

Example 61

[0381] 2-(2-Acetylphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether,Trifluoroacetate

[0382] The title compound was prepared starting from2-hydroxyacetophenone (170 mg, 1.25 mmol) and2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (325mg, 1 mmol; prepared in Example 52, Step 2), but no extraction with NaOHand without the third chromatographic step, to give 170 mg (37%) of thetrifluoroacetate. HRMS m/z calcd for C₁₈1H₂₂N₄O₃ (M)⁺ 342.1692, found342.1704.

Example 62

[0383] 2-(2-Acetyl-5-methoxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether, Trifluoroacetate.

[0384] The title compound was prepared starting from2-hydroxy-4-methoxy-acetophenone (208 mg, 1.25 mmol) and2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (325mg, 1 mmol; prepared in Example 52, Step 2), but no extraction with NaOHand without the third chromatographic step, to give 128 mg (26%) of thetrifluoroacetate. HRMS m/z calcd for C₁₉H₂₄N₄O₄ (M)⁺ 372.1798, found372.1810.

Example 63

[0385] 2-(2-Acetyl-3,5-dimethoxyphenoxy)ethyl3-(1-piperazinyl)-2-pyrazinyl ether, Trifluoroacetate.

[0386] The title compound was prepared starting from2-hydroxy-4,6-dimethoxyacetophenone (245 mg, 1.25 mmol) and2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (325mg, 1.00 mmol; prepared in Example 52, Step 2), but no extraction withNaOH and without the third chromatographic step, to give 216 mg (42%) ofthe trifluoroacetate. HRMS m/z calcd for C₂₀H₂₆N₄O₅ (M)⁺ 402.1903, found402.1886.

Example 64

[0387] 2-(5,6,7,8-Tetrahydro-2-naphthyloxy)ethyl3-(1-piperazinyl)-2-pyrazinyl ether, Trifluoroacetate.

[0388] The title compound was prepared starting from5,6,7,8-tetrahydro-2-naphthol (185 mg, 1.25 mmol) and2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (325mg. 1.00 mmol; prepared in Example 52, Step 2), but no extraction withNaOH and without the third chromatographic step, to give 155 mg (33%) ofthe trifluoroacetate. HRMS m/ calcd for C₂₀H₂₆N₄O₂ (M)⁺ 354.2056, found354.2068.

Example 65

[0389] 2-(2-Fluoro-6-methoxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether.

[0390] The title compound was prepared starting from2-fluoro-6-methoxyphenol (178 mg, 1.25 mmol) and2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.17mmol; prepared in Example 52, Step 2) to give 230 mg (66%) of a yellowoil.

[0391] HRMS m/z calcd for C₁₇H₂₁FN₄O₃ (M)⁺ 348.1598, found 348.1602.

Example 66

[0392] 2-(2-Methoxy-4-methylphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether.

[0393] The title compound was prepared starting from2-methoxy-4-methylphenol (162 mg, 1.25 mmol) and2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.00mmol; prepared in Example 52, Step 2) to give 233 mg (67%) of a yellowsolid. HRMS m/z calcd for C₁₈H₂₄N₄O₃ (M)⁺ 344.1848, found 344.1839.

Example 67

[0394] 7-Isoquinolinyl 2-{[3-(1-piperazinyl)]-2-pyrazinyl}oxy)ethylether, Difumarate

[0395] The title compound was prepared starting from7-hydroxyisoquinoline (435 mg, 3.00 mmol) and2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.00mmol; prepared in Example 52, Step 2). The free base of the titlecompound was converted to its fumarate salt. Yield 45 mg (2%); mp 157°C. (dec). HRMS m/z calcd for C₁₉H₂₁N₅O₂ (M)⁺ 351.1695, found 351.1695.Anal. (C₁₉H₂₁N₅O₂.2.3 C₄H₄O₄).

Example 68

[0396] 2-(2-Chloro-4-methoxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether.

[0397] The title compound was prepared starting from2-chloro-4-methoxyphenol (103 mg, 0.65 mmol) and2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (0.61mmol; prepared in Example 52, Step 2) according to the proceduredescribed in Example 52, Step 3, but utilizing diethyl azodicarboxylate(DEAD) instead of TMAD.

[0398] Yield 50 mg (21%). HRMS ml calcd for C₁₇H₂₁ClN₄O₃ (M)⁺ 364.1302,found 364.1307.

Example 69

[0399]2-{2-[2-Fluoro-5-(trifluoromethyl)phenoxy]ethoxy}-3-(1-piperazinyl)pyrazine.

[0400] 2-Fluoro-5-(trifluoromethyl)phenol (0.54 g, 3.0 mmol) was addedto a stirred solution of DEAD (0.52 g, 3.0 mmol), PPh₃ (0.79 g, 3.0mmol) and2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (0.49g, 1.5 mmol; prepared in Example 52, Step 2) in THF (50 mL). Thereaction mixture was stirred at room temperature overnight. The solventwas evaporated and the residue was purified by column chromatography onsilica using isohexane/EtOAc (80:20) as eluent. The N-Boc protectedintermediate obtained was treated with CH₂Cl₂/TFA (75:25; 5 mL) for 1 hat room temperature and concentrated. The residue was purified by columnchromatography on silica using EtOAc/MeOH/Et₃N (80:15:5) as eluent togive 0.22 g (38%) of the title compound. MS m/z 387 (M+H)⁺. HRMS m/zcalcd for C₁₇H₁₈F₄N₄O₂ (M)⁺ 386.1366, found 386.1367.

Example 70

[0401]8-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-2H-1,4-benzoxazin-3(4H)-one,Maleate.

[0402] Step 1: 8-Hydroxy-2H-1,4-benzoxazin-3(4H)-one.

[0403] The title compound was prepared according to procedure describedin J. Med. Chem. 1996, 39, 3533-3538 by replacing 2-amino-m-cresol with3-amino-pyrocatechol.* The crude product was purified by columnchromatography on silica gel using EtOAc/isohexane (1:2 to 2:1) aseluent. Solid; yield 70%. MS m/z 165 (M)⁺. Anal. (C₈H₇NO₃) C, H, N.

[0404] Step 2:8-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-2H-1,4-benzoxazin-3(4H)-one,Maleate.

[0405] The title compound was prepared according to the procedure ofExample 69 starting from the product of Step 1 above. Yield 42%. MS m/z372 (M+H)⁺. Anal. (C₁₈H₂₁N₅O₄.C₄H₄O₄) C, H, N.

Example 71

[0406]2-{2-[3-(Methylsulfonyl)phenoxy]ethoxy}-3-(1-piperazinyl)pyrazine.

[0407] Step 1: 3-(Methylsulfonyl)phenol.

[0408] The title compound was prepared by a slightly modified literatureprocedure.* 3-aminophenyl methyl sulfone hydrochloride (1.18 g, 5.70mmol) was suspended in water/CH₂Cl₂. The mixture was neutralized with25% aqueous NaOH. The CH₂Cl₂ layer was isolated and evaporated todryness. Aqueous H₂SO₄ (60%; 10 mL) was added to the residue and thesolution was cooled to 0° C. A solution of NaNO₂ (0.345 g, 5.00 mmol) inwater (5 mL) was added dropwise. The solution was stirred at 0° C. for30 min. and at 90° C. for 30 min. The reaction mixture was allowed tocome to room temperature. Extraction with CH₂Cl₂, drying (MgSO₄), andconcentration gave 0.39 g (40%) of the title compound as a solid. MS m/z172 (M)⁺. HRMS m/z calcd for C₇H₈₀₃S (M)⁺ 172.0194, found 172.0198.

[0409] Step 2,2-{2-[3-(Methylsulfonyl)phenoxy]ethoxy}-3-(1-piperazinyl)pyrazine.

[0410] The title compound was prepared according the procedure ofExample 69 starting from the product of Step 1. Yield 26%. MS m/z 379(M+H)⁺. HRMS m/z calcd for C₁₇H₂₂N₄O₄S (M)⁺ 378.1362, found 378.1343.

Example 72

[0411]7-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-2H-chromen-2-one.

[0412] The title compound was prepared according to the procedure ofExample 69 starting from 7-hydroxy-2H-chromen-2-one. Yield 29%. MS m/z369 (M+H)⁺. HRMS m/z calcd for C₁₉H₂₀N₄O₄ (M)⁺ 368.1485, found 368.1478

Example 73

[0413] 2-(2,3,6-Trifluorophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether.

[0414] The title compound was prepared according to the procedure ofExample 69 starting from 2,3,6-trifluorophenol. Yield 46%. MS m/z 355(M+H)⁺. HRMS m/z calcd for C₁₆H₁₇F₃N₄O₂ (M)⁺ 354.1304, found 354.1288.

Example 74

[0415] 2-(2,4,5-Trifluorophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether.

[0416] The title compound was prepared according to the procedure ofExample 69 starting from 2,4,5-trifluorophenol. Yield 43%. MS m/z 355(M+H)⁺. HRMS nm/z calcd for C₁₆H₁₇F₃N₄O₂ (M)⁺ 354.1304, found 354.1304.

Example 75

[0417] 2-(2-Hydroxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether.

[0418] The title compound was prepared according to the procedure ofExample 69 starting from catechol. Yield 37%. MS m/z 317 (M+H)⁺. HRMSm/z calcd for C₁₆H₂₀N₄O₃ (M)-316.1535, found 316.1535.

Example 76

[0419] 2-(3-Hydroxyphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether.

[0420] The title compound was prepared according to the procedure ofExample 69 starting from resorcinol. Yield 36%. MS m/z 317 (M+H)⁺. HRMSm/z calcd for C₁₆H₂₀N₄O₃ (M)⁺ 316.1535, found 316.1525.

Example 77

[0421] 2-[3-(4-Morpholinyl)phenoxy]ethyl 3-(1-piperazinyl)-2-pyrazinylether. 1,1′-Azobis(N,N-dimethylformamide) (TMAD; 256 mg, 1.50 mmol) wasadded to a solution of2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (400mg. 1.24 mmol; prepared in Example 52, Step 2), 3-(4-morpholinyl)phenol(441 mg, 1.23 mmol) and triphenylphosphine (646 mg, 2.46 mmol) in THF (3mL). The reaction mixture was stirred at room temperature for 2.5 h andthen concentrated. The residue was purified by repeated chromatographyon silica gel using toluene and toluene/EtOAc (8:2) as eluents. Solventswere evaporated and the residue was treated with CH₂Cl₂/TFA/H₂O(1:0.9:0.1; 5 mL) at room temperature for 0.5 h. After concentration. 5M NaOH was added followed by extraction with CH₂Cl₂. The organic phasewas dried (K₂CO₃), filtered, and concentrated. The residue was purifiedby chromatography on silica gel using CHCl₃/MeOH (9:1) as eluent to give50 mg (10%) of the title product as on oil. HRMS m/z calcd forC₂OH)₇N₅O₃ (M)⁺ 385.2114, found 385.2100.

[0422] Examples 78-82 were prepared according to the procedure ofExample 77 starting from2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol andthe requisite phenolic compound.

Example 78

[0423] 2-(1,3-Benzodioxol-4-yloxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether.

[0424] The title compound was prepared starting from1,3-benzodioxol-4-ol* (340 mg, 1.24 mmol) to give 125 mg (29%) of anoil. HRMS m/z calcd for C₁₇H₂₀N₄O₄ (M)⁺ 344.1485, found 344.1487.

Example 79

[0425] 2-(2,3-Dihydro-1,4-benzodioxin-5-yloxy)ethyl3-(1-piperazinyl)-2-pyrazinyl ether.

[0426] The title compound was prepared starting from2,3-dihydro-1,4-benzodioxin-5-ol* (374 mg, 1.24 mmol) to give 260 mg(59%) of a solid: mp 98-99° C. HRMS m/z calcd for C₁₈H₂₂N₄O₄ (M)⁺358.1641, found 358.1648.

Example 80

[0427] 2-(2-Allylphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether.

[0428] The title compound was prepared starting from 2-allylphenol (330mg, 1.24 mmol) to give 200 mg (47%) of an oil. HRMS m/z calcd forC₁₉H₂₄N₄O₂ (M)⁺ 340.1899, found 340.1888.

Example 81

[0429] 2-(3-Aminophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether.

[0430] The title compound was prepared starting from 3-aminophenol (268mg, 1.24 mmol) to give 49 mg (13%) of an oil. HRMS m/z calcd forC₁₆H₂₁N₅O₂ (M) 315.1695, found 315.1705.

Example 82

[0431] 2-(1-Oxoindanyl-4-yloxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether.

[0432] The title compound was prepared starting from4-hydroxy-1-indanone (365 mg, 1.24 mmol) to give 19 mg (4%) of an oil.HRMS m/z calcd for C₁₉H₂₂N₄O₃ (M)⁺ 354.1692, found 354.1705.

Example 83

[0433] 2-(2,6-Difluorophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether.

[0434] The title compound was prepared according to the procedure ofExample 77 starting from 2,6-difluorophenol (239 mg, 1.84 mmol), TMAD(384 mg, 2.25 mmol),2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (600mg, 1.86 mmol; prepared in Example 52, Step 2), and triphenylphosphine(969 mg, 3.69 mmol) to give 279 mg (45%) of a solid: mp 101-102° C. HRMSm/z calcd for C₁₆H₁₈F₂N₄O₂ (M)+336.1398, found 336.1403.

Example 84

[0435]5-Nitro-8-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)quinoline,Hydrochloride. DEAD (0.485 mL, 3.08 mmol) was added to a stirredsolution of 2-[3-(4-tert-2sbutoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.00 g, 3.08 mmol;prepared in Example 52, Step 2), 8-hydroxy-5-nitroquinoline (0.589 g,3.08 mmol) and PPh₃ (0.85 g, 3.24 mmol) in THF (10 mL). The mixture wasstirred at room temperature for 2 h, and concentrated. The residue waspassed through a silica column using toluene/EtOAc (1:1) as eluent. TheN-Boc protected intermediate obtained was treated with CH₂Cl₂/TFA/H₂O(50:45:5; 15 mL) for 30 min at room temperature and concentrated. Theresidue was dissolved in 0.1 M aqueous HCl and washed with toluene. Thewater phase was concentrated to give 0.206 g (15%) of the title product.Pos-E1-N4S shows M⁻ and 7 ions supporting the stated structure: HRMS m/zcalcd for C₁₉H₁₀N₆O₄ (M)⁺ 396.1546, found 396.1557.

Example 85

[0436]6-Methoxy-7-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-2H-chromen-2-one,Dihydrochloride.

[0437] DEAD (0.50 mL, 3.2 mmol) was added dropwise to a stirred mixtureof 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol(1.00 g, 3.08 mmol; prepared in Example 52, Step 2), scopoletin (0.60 g,3.1 mmol) and triphenylphosphine (0.87 g, 3.3 mmol) in THF (10 mL) atroom temperature. After 1 h, the reaction mixture was diluted with EtOAcand washed with water. The organic phase was dried, (MgSO₄),concentrated and the residue was purified by column chromatography onsilica using toluene/EtOAc (7:3) as eluent. The pure fractions werecombined and treated with CH₂Cl₂/TFA/H₂O (50:45:5; 5 mL) for 30 min atroom temperature. The mixture was diluted with 0.2 M aqueous HCl andwashed with EtOAc (×3). The aqueous layer was concentrated to give 0.075g (5%) of the title product. Pos-EI-MS shows M+ and 15 ions supportingthe stated structure. Anal (C₂₀H₂₂N₄O₅.1.3 HCl.1.4H₂O)C, H, N.

Example 86

[0438]4-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-2,1,3-benzothiadiazole,Dihydrochloride.

[0439] Step 1: tert-Butyl4-{3-[2-(2,1,3-benzothiadiazol-4-yloxy)ethoxy]-2-pyrazinyl}-1-piperazinecarboxylate.

[0440] DEAD (0.52 mL, 3.3 mmol) was added to a slurry of2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.00g, 3.08 mmol; prepared in Example 52, Step 2).4-hydroxy-2,13-benzothiadiazole* (0.46 g. 3.0 mmol) and resin bound PPh₃(1.1 g. 3.3 mmol) and shaken until HPLC showed no starting material. Themixture was filtered to remove the resin, concentrated and purified bycolumn chromatography on silica to give 0.163 g (12%) of the titlecompound. Pos-EI-MS shows M+ and 11 ions supporting the statedstructure. HRMS ni/z calcd for C₂₁H₂₆N₆O₄S (M)⁺ 458.1736, found458.1716.

[0441] Step 2:4-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-2,1,?3-benzothiadiazole,Dihydrochloride.

[0442] The product from Step 1 above (0.163 g, 0.356 mmol) was treatedwith CH₂Cl₂/TFA/1H₂O (50:45:5; 5 mL) at room temperature for 30 min. Thereaction mixture was concentrated and diluted with 0.1 M aqueous HCl andwashed with toluene. The water phase was concentrated and the residuecrystallized from MeOH/diethyl ether to give 0.088 g (57%) of the titleproduct. Pos-EI-MS shows M⁺ and 7 ions supporting the stated structure;HRMS m/z calcd for C₁₆H₁₈N₆O₂S (M)⁺ 358.1212, found 358.1207. Anal(C₁₆H₁₈N₆O₂S.2HCl.H₂O)C, H, N.

Example 87

[0443] 8-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)quinazoline,Maleate.

[0444] DEAD (0.657 mL, 4.00 mmol) was added to a stirred solution of8-quinazolinol* (0.55 g, 3.76 mmol),2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.216g, 3.75 mmol; prepared in Example 52, Step 2) and PPh₃ (1.048 g, 4.00mmol) in THF (12 mL). The reaction was stirred at room temperature for 2h and then poured into 5% aqueous NaOH and extracted with EtOAc. Theorganic layer was dried (MgSO₄) and concentrated. The residue waspurified by column chromatography on silica using toluene/EtOAc/MeOH(49:50:1). The pure fractions were combined and treated withCH₂Cl₂/TFA/H₂O (50:45:5; 5 mL) at room temperature for 30 minutes,poured into 0.5 M aqueous HCl and washed with EtOAc. The water phase wasalkalinized to pH 12 and extracted with EtOAc, dried (MgSO₄), andconcentrated to give 0.499 g (1.40 mmol) of the free base of the titlecompound. The free base was dissolved in dioxane (10 mL), and maleicacid (0.162 g. 1.40 mmol) in dioxane (2 mL) was added and the solutionconcentrated to give 0.65 g (37%) of the title product. Pos-EI-MS showsM⁺ and 9 ions supporting the stated structure. Anal (C₁₈H₂₀N₆O₂.1.3C₄H₄O₄) C, H, N.

Example 88

[0445] 5-(2-{[3-(1-Piperazinyl)-2-pyrazinyl]oxy}ethoxy)quinoxaline,Hydrochloride.

[0446] TMAD (0.55 g, 3.20 mmol) was added to a stirred solution of2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.00g, 3.08 mmol; prepared in Example 52, Step 2), 5-hydroxyquinoxaline*(0.45 g, 3.08 mmol) and PPh₃ (0.85 g, 3.24 mmol) in THF (20 mL). Thereaction was stirred at room temperature for 1.5 h and at 65° C. for 2h. The reaction mixture was concentrated and the residue was purified bycolumn chromatography on silica using toluene/EtOAc (1:1) as eluent. Theresulting solid was crystallized twice from diethyl ether/petroleumether to remove PPh₃O. The recrystallized material (0.50 g) wasdissolved in MeOH (15 mL) and 1 M HCl (3.5 mL) was added. The resultingmixture was stirred at room temperature for 4 h (only 10%N-Boc-deprotection had occurred according to HPLC/MS). The mixture wasconcentrated and the residue was treated with CH₂Cl₂/TFA/H₂O (50:45:5;20 mL) for 1 h. After concentration in vacuo, the residue was dissolvedin 0.1 M aqueous HCl and washed with toluene. The water phase waslyophilized to give a yellow oil that was dissolved in 1 M HCl. Thesolution was concentrated and MeOH and diethyl ether was added. Theprecipitate formed was collected and dried in vacuum to give 0.32 g(76%) of the title product. Pos-EI-MS shows M+ and 8 ions supporting thestated structure. HRMS m/z calcd for C₁₈H₂₀N₆O₂ (M)⁺ 352.1648, found352.1662.

Example 89

[0447]1-[7-(2-([3-(1-piperazinyl)-2-pyrazinyl]oxyethoxy)-1-benzofuran-2-yl]-1-ethanone,Hydrochloride.

[0448] DEAD (0.787 mL, 5.00 mmol) was added to a stirred solution of2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.50g, 4.63 mmol; prepared in Example 52, Step 2),2-acetyl-7-hydroxybenzofuran (0.88 g, 5.0 mmol) and PPh₃ (1.31 g, 5.0mmol) in THF (3 mL) under gentle heating. After being stirred for 30 minat room temperatue, the reaction mixture was poured into water,extracted with EtOAc, dried (MgSO₄) and concentrated. The residue waspurified by column chromatography on silica using toluene/EtOAc (7:3) aseluent. The pure fractions were combined and treated with CH₂Cl₂/TFA/H₂O(50:45:5; 5 mL) for 30 min at room temperature. The mixture was pouredinto 0.5 M aqueous HCl and washed with EtOAc. The aqueous layer wasalkalinized, by addition of NaOH, to pH 12 and extracted with EtOAc. Theorganic layer was dried (MgSO₄), filtered and concentrated. The residue(0.250 g, 0.65 mmol) and pyridinium hydrochloride (0.075 g, 0.65 mmol)was dissolved in MeOH. The mixture was and concentrated and the residuewas re-dissolved in EtOH and concentrated three more times to give 0.27g (14%) of the title product. Pos-EI-MS shows M+ and 19 ions supportingthe stated structure. HRMS m/z calcd for C₂₀H₂₂N₄O₄ (M)⁺ 382.1641, found382.1631.

Example 90

[0449] 3-(Phenoxy)propyl 3-(1-piperazinyl)-2-pyrazinyl ether,Dihydrochloride.

[0450] Step 1: 2-Chloro-3-(1-piperazinyl)pyrazine.*

[0451] A mixture of 2,3-dichloropyrazine (1.35 g, 15.32 mmol),piperazine (2.34 g, 27.2 mmol) and K₂CO₃ (1.25 g, 9.04 mmol) inacetonitrile (5.5 mL) was stirred at 110° C. for 1.25 h in a sealedtube. The reaction mixture was diluted with CH₂Cl₂, filtered, andconcentrated to give a yellowish semisolid residue which was purified bychromatography on silica gel using CHCl₃/MeOH (9:1) as eluent. Theobtained solid was redissolved in CHCl₃ and applied to a short (3 cm)plug of alumina. Elution with ether/CHCl₃ (9:1) afforded 1.24 g (69%) ofthe title product as a white solid: mp 47-53° C. HRMS m/z calcd forC₈H₁₁CIN₄ (M)⁺ 198.0672, found 198.0673.

[0452] Step 2: 3-(Phenoxy)propyl 3-(1-piperazinyl)-2-pyrazinyl ether,Dihydrochloride.

[0453] 2-Chloro-3-(1-piperazinyl)pyrazine (608 mg. 3.1 mmol, from Step 1above) and 3-phenoxypropanol (570 mg, 3.7 mmol) was dissolved in dioxane(10 mL). KO-t-Bu (870 mg, 7.7 mmol) was added and the mixture wasstirred at 95° C. for 6 h. The solvent was evaporated and the residuewas purified by chromatography on silica gel using CH₂Cl₂/MeOH (9:1) aseluent to give the free base of the title compound as a yellow oil. Thefree base was converted to the dihydrochloride salt: yield 0.3S0 g(32%); mp 146-146.5° C. Anal. (C₁₇H₂₂N₄O₂.2HCl) C, H, N.

[0454] Examples 91-161 were prepared according to the procedure ofExample 90, Step 2, starting from 2-chloro-3-(1-piperazinyl)pyrazine andthe appropriate alcohol. Purification was by column chromatography onsilica gel using CHC₃/MeOH (9:1) or CHCl₃/MeOH/NH₄OH (95:5:0.5) or otherappropriate solvent system.

Example 91

[0455] 2-(2-Trifluoromethylphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether.

[0456] Step 1: 2-(2-Trifluoromethylphenoxy)ethanol.

[0457] A mixture of 2-trifluoromethylphenol (2.00 g, 12.3 mmol), K₂CO₃(1.71 g, 12.3 mmol) and ethylene carbonate (1.20 g, 13.6 mmol) in dryDMF (30 mL) was heated at 150° C. for 1 h. After cooling, the reactionwas quenched by addition of water (10 mL). The mixture was concentratedin vacuo and the residue partitioned between water (30 mL) and EtOAc (30mL). The aqueous phase was extracted with additional portions of EtOAc(3×30 mL). The combined organic layers were treated with charcoal, driedover MgSO₄, and filtered through Celite. The filtrate was concentratedin vacuo and the remaining oil was purified by chromatography on silicagel using n-hexane/EtOAc (80:20) as eluent to give 0.50 g (20%) of thetitle product as white crystals: mp 74-77° C. Anal. (C₉H₉F₃O₂) C, H.

[0458] Step 2: 2-(2-Trifluoromethylphenoxy)ethyl3-(1-piperazinyl)-2-pyrazinyl ether. Yield 48%; mp 79-80° C. Anal.(C₁₇H₁₉F₃N₄O₂) C, H, N.

Example 92

[0459] 2-(2-Methylthiophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether,Maleate.

[0460] Step 1: 2-(2-Methylthiophenoxy)ethanol.*

[0461] The title compound was prepared according to the proceduredescribed in Example 91, Step 1, starting from 2-(methylthio)phenol.Yield 63%: mp 47-49° C. Anal. (C₉H₁₂O₂S) C. H.

[0462] Step 2: 2-(2-Methylthiophenoxy)ethyl3-(1-piperazinyl)-2-pyrazinyl ether, Maleate.

[0463] Yield 68%; mp 160-162° C. Anal. (C₁₇H₂₂N₄O₂S.C₄H₄O₄.0.1 THF) C,H, N.

Example 93

[0464] 2-(2-Methylphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether,Maleate.

[0465] Step 1: 2-(2-Methylphenoxy)ethanol.*

[0466] The title compound was prepared according to the proceduredescribed in Example 91, Step 1, starting from o-cresol. Oil; yield 59%.HRMS m/z calcd for C₉H₁₂O₂ (M)⁺ 152.0837, found 152.0840.

[0467] Step 2: 2-(2-Methylphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether, Maleate.

[0468] Yield 33%; mp 151-152° C. Anal. (C₁₇H₂₂N₄O₂.C₄H₄O₄.0.5H₂O)C, H,N.

Example 94

[0469] 2-(2,5-Dimethylphenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether.

[0470] Step 1: 2-(2,5-Dimethylphenoxy)ethanol.*

[0471] The title compound was prepared according to the proceduredescribed in Example 91, Step 1, starting from 2,5-dimethylphenol. Yield60%; mp 45-48° C. Anal. (C₁₀H₁₄O₂) C, H.

[0472] Step 2: 2-(2,5-Dimethylphenoxy)ethyl3-(1-piperazinyl)-2-pyrazinyl ether. Oil; yield 65%. Anal. (C₁₈H₂₄N₄O₂)C, H, N.

Example 95

[0473] 2-(2-Fluorophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether,Maleate.

[0474] Step 1: 2-(2-Fluorophenoxy)ethanol.*

[0475] The title compound was prepared according to the proceduredescribed in Example 91. Step 1, starting from 2-fluorophenol. Oil;yield 71%. MS m/z 156 (M)₄.

[0476] Step 2: 2-(2-Fluorophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether, Maleate. Yield 46%; mp 171-173° C. Anal. (C₁₆H₁₉FN₄O₂.C₄H₄O₄) C,H, N.

Example 96

[0477] 2-(2-Cyanophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether,Maleate.

[0478] Step 1: 2-(2-Cyanophenoxy)ethanol.*

[0479] The title compound was prepared according to the proceduredescribed in Example 91, Step 1, starting from 2-cyanophenol. Oil; yield26%. MS m/z 163 (M)⁺.

[0480] Step 2: 2-(2-Cyanophenoxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether, Maleate. Yield 40%; mp 165-166° C. Anal. (C₁₇H₁₉N₅O₂.C₄H₄O₄) C,H, N.

Example 97

[0481] 2-[(,1′Biphenyl)-2-yloxy]ethyl 3-(1-piperazinyl)-2-pyrazinylether.

[0482] Step 1: 2-[(1,1′Biphenyl)-2-yloxy]ethanol.*

[0483] The title compound was prepared according to the proceduredescribed in Example 91, Step 1, starting from 2-phenylphenol. Yield52%; mp 71-75° C. Anal. (C₁₄H₁₄O₂) C, H.

[0484] Step 2: 2-[(1,1′Biphenyl)-2-yloxy]ethyl3-(1-piperazinyl)-2-pyrazinyl ether. Yield 53%; mp 101-103° C. Anal.(C₂₂H₂₄N₄O₂) C, H, N.

Example 98

[0485] 4-(Phenoxy)butyl 3-(1-piperazinyl)-2-pyrazinyl ether,Dihydrochloride.*

[0486] Yield 49%; mp 129-131° C. Anal. (C₁₈H₂₄N₄O₂ 2HCl) C, H, N.

Example 99

[0487] 2-[2-(2-Fluoro-5-methylphenoxy)ethoxy]-3-(1-piperazinyl)pyrazine,Fumarate.

[0488] Step 1: 2-(2-Fluoro-5-methylphenoxy)ethanol.

[0489] The title compound was prepared according to the proceduredescribed in Example 91. Step 1, starting from 2-fluoro-5-methylphenol.Oil; yield 94%. MS m/z 170 (M)⁺.

[0490] Step 2:2-[2-(2-Fluoro-5-methylphenoxy)ethoxy]-3-(1-piperazinyl)pyrazine,Fumarate.

[0491] Yield 71%; mp 145-146° C. Anal. (C₂₁H₂₅FN₄O₆.0.3H₂O) C, H, N.

Example 100

[0492]2-[2-(5-Fluoro-2-methoxyphenoxy)ethoxy]-3-(1-piperazinyl)pyrazine,Fumarate.

[0493] Step 1: 2-(5-Fluoro-2-methoxyphenoxy)ethanol*.

[0494] The title compound was prepared according to the proceduredescribed in Example 91, Step 1, starting from5-fluoro-2-methoxyphenol**. Yield 89%. MS m/z 186 (M)⁺. Anal. (C₉H₁₁FO₃)C, H.

[0495] Step 2:2-[2-(5-Fluoro-2-methoxyphenoxy)ethoxy]-3-(1-piperazinyl)pyrazine,Fumarate.

[0496] Yield 76%; mp 172-176° C. Anal. (C₁₇H₂₁FN₄O₃ C₄H₄O₄ 0.3H₂O)C, H,N.

Example 101

[0497] 2-[2-(3-Fluorophenoxy)ethoxy]-3-(1-piperazinyl)pyrazine, Maleate.

[0498] Step 1: 2-(3-Fluorophenoxy)ethanol*.

[0499] The title compound was prepared according to the proceduredescribed in Example 91, Step 1, starting from 3-fluorophenol. Oil;yield 83%. MS m/z 156 (M).

[0500] Step 2: 2-[2-(3-Fluorophenoxy)ethoxy]-3-(1-piperazinyl)pyrazine,Maleate.

[0501] Solid, yield 51%; mp 141-143° C. Anal. (C₁₆H₁₉FN₄O₂.C₄H₄O₄) C, H,N.

Example 102

[0502] 2-[2-(3-Methoxyphenoxy)ethoxy]-3-(1-piperazinyl)pyrazine,p-Toluenesulfonate.

[0503] Step 1: 2-(3-Methoxyphenoxy)ethanol*.

[0504] The title compound was prepared according to the proceduredescribed in Example 91. Step 1, starting from 3-methoxyphenol. Oil;yield 64%; MS m/z 168 (M)⁺. Anal. (C₉H₁₂O₃) C, H.

[0505] Step 2: 2-[2-(3-Methoxyphenoxy)ethoxy]-3-(1-piperazinyl)pyrazine,p-Toluenesulfonate.

[0506] Solid; yield 20%; mp 131-133° C. Anal. (C₁₇H₂₂N₄O₃ C₇H₈O₃S) C, H,N.

Example 103

[0507] 2-[2-(3-Acetylphenoxy)ethoxy]-3-(1-piperazinyl)pyrazine.

[0508] Step 1: 2-(3-Acetylphenoxy)-1-ethanol.*

[0509] The title compound was prepared according to the proceduredescribed in Example 91. Step 1, starting from 3-hydroxyacetophenone.Oil; yield 82%. MS m/z 180 (M). HRMS m/z calcd for C₁₀H₁₂O₃ (M)⁺180.0786, found 180.0787.

[0510] Step 2: 2-[2-(3-Acetylphenoxy)ethoxy]-3-(1-piperazinyl)pyrazine,Maleate.

[0511] Yield of free base 68%. Part of the free base was converted tothe maleate salt. MS n, 343 (M+H)⁺. Anal. (C₁₈H₂₂N₄O₃ C₄H₄O₄) C, H, N.

Example 104

[0512] 2-[2-(3-Cyanophenoxy)ethoxy]-3-(1-piperazinyl)pyrazine.

[0513] Step 1: 2-(3-Cyanophenoxy)-1-ethanol.*

[0514] The title compound was prepared according to the proceduredescribed in Example 91, Step 1, starting from 3-cyanophenol. Oil, yield63%. MS m/z 163 (M)⁺. Anal. (C₉H₉NO₂) C, H, N.

[0515] Step 2: 2-[2-(3-Cyanophenoxy)ethoxyl]-3-(1-piperazinyl)pyrazine.Solid; yield 74%. MS m/z 326 (M+H)⁺. Anal. (C₁₇H₁₉N₅O₂) C, H, N.

Example 105

[0516] 2-[2-(2,3-Difluorophenoxy)ethoxy]-3-(1-piperazinyl)pyrazine,Fumarate.

[0517] Step 1: 2-(2,3-Difluorophenoxy)-1-ethanol.

[0518] The title product was prepared according to the proceduredescribed in Example 91, Step 1, starting from 2,3-difluorophenol. Oil;yield 92%. MS m/z 174 (M)⁺. Anal (C₈H₈F₂O₂) C, H.

[0519] Step 2:2-[2-(2,3-Difluorophenoxy)ethoxy]-3-(1-piperazinyl)pyrazine, Fumarate.

[0520] Yield 35%; mp 125-130° C. Anal. (C₁₆H₁₈F₂N₄O₂.C₄H₄O₄) C, H, N.

Example 106

[0521] 2-[2-(2,3,5-Trifluorophenoxy)ethoxy]-3-(1-piperazinyl)pyrazine,Fumarate.

[0522] Step 1: 2-(2,3,5-Trifluorophenoxy)-1-ethanol.

[0523] The title product was prepared according to the proceduredescribed in Example 91, Step 1, starting from 2,3,5-trifluorophenol.Oil; yield 83%. MS m/z 192 (M)⁺. Anal. (C₈H₇F₃O₂) C, H.

[0524] Step 2:2-[2-(2,3,5-Trifluorophenoxy)ethoxy]-3-(1-piperazinyl)pyrazine,Fumarate.

[0525] Yield 35%; mp 158-159° C. MS m/z 354 (M)⁺; HRMS m/z calcd forC₁₆H₁₇F₃N₄O₂ (M)⁺ 354.1304, found 354.1303. Anal. (C₁₆H₁₇F₃N₄O₂.C₄H₄O₄)C, H. N.

Example 107

[0526] N-Phenyl-3-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)aniline,Fumarate.

[0527] Step 1: 2-(3-Anilinophenoxy)-1-ethanol.*

[0528] The title product was prepared according to the proceduredescribed in Example 91. Step 1, starting from 3-anilinophenol. Oil:yield 75% o HRMS n/?7Z calcd for C₁₄H₁₅NO₂ (M)⁺ 229.1103, found229.1111.

[0529] Step 2:N-Phenyl-3-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)aniline,Fumarate.

[0530] Yield of free base 24%. Part of the base was converted into itsfumarate salt: mp 78-81° C.; HRMS m/z calcd for C₂₂H₂₅N₅O₂ (M)⁺391.2008, found 391.2001. Anal (C₂₂H₂₅N₅O₂.C₄H₄O₄) C, H, N.

Example 108

[0531] [3-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)phenyl]methanol,Maleate.

[0532] Step 1: 3-(2-Hydroxyethoxy)benzaldehyde*

[0533] The title product was prepared according to the proceduredescribed in Example 91, Step 1, starting from 3-hydroxybenzaldehyde.Oil; yield 88%; MS m/z 166 (M)⁺. Anal. (C₉H₁₀O₃.0.2H₂O)C, H, N.

[0534] Step 2: 2-[3-(Dimethoxymethyl)phenoxy]-1-ethanol.

[0535] p-TsOH (165 mg, 0.87 mmol) was added to a solution of the productobtained in Step 1 (1.45 g, 8.73 mmol) in dry MeOH (60 mL). After beingstirred for 23 h at room temperature, more p-TsOH (170 mg, 0.89 mmol)was added. After additional 4 h of stirring, the reaction was quenchedby the addition of NaHCO₃ (saturated aqueous solution, 70 mL) and H₂O(50 mL). The aqueous phase was extracted with EtOAc (3×100 mL). Thecombined organic phases were washed with brine and dried (MgSO₄).Evaporation of the solvents afforded a yellow oil that was used in thenext step without purification. Yield 1.59 g (86%). The productcontained about 5% of starting material (¹H NMR).

[0536] Step 3:2-{2-[3-(Dimethoxymethyl)phenoxy]ethoxy}-3-(1-piperazinyl)pyrazine. Oil;yield 63%: MS m/z 344 (M—CH₂O). HRMS m/z calcd for C₁₈H₂₄N₄O₃ (M—CH₂O)⁺344.1848, found 344.1847.

[0537] Step 4:3-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)benzaldehyde.

[0538] HOAc (12 mL) and H₂O (4 mL) was added to a solution of theproduct obtained in Step 3 (858 mg, 2.29 mmol) in THF (4 mL). Thereaction mixture was stirred at 45° C. for 1.5 h and then diluted withEtOAc (150 mL). The organic phase was washed with brine (x 2), aqueoussaturated NaHCO₃ and brine. Drying (MgSO₄) followed by evaporation ofthe solvents afforded the title product (0.41 g) as an acetate salt (1.7HOAc as determined by ¹H NMR). This product was used in the next stepwithout purification.

[0539] Step 5:[3-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)phenyl]methanol,Maleate.

[0540] The product obtained in Step 4 (408 mg, 1.24 mmol) was dissolvedin EtOH (99%, 35 mL). Immediately upon addition of NaBH₄ (293 mg, 7.75mmol) the solution turned white. The reaction mixture was stirred atroom temperature for 5 h and then quenched by addition of H₂O (7 mL).The mixture was filtered, and the filtrate diluted with aqueoussaturated NaCl (30 mL) and H₂O (20 mL). The aqueous solution wasextracted with EtOAc (×4). The combined organic phases were washed withbrine and dried (MgSO₄). Evaporation of the solvents gave a semi-solidresidue (330 mg) that was purified by column chromatography on silicausing gradient elution with EtOAc/MeOH (9:1)+1% NH₃ to EtOAc/MeOH(8:2)+1% NH₃. This afforded 76 mg (16%) of the free base of the titleproduct as a semi-solid which was converted to its maleate salt: mp123.2-123.5° C.; MS m/z 331 (M+H)⁺. HRMS m/z calcd for C₁₇H₂₂N₄O₃ (M)⁺330.1692, found 330.1692.

Example 109

[0541] 2-{2-[3-(Methoxymethyl)phenoxy]ethoxy}-3-(1-piperazinyl)pyrazine,Maleate.

[0542] Step 1: 2-[3-(Methoxymethyl)phenoxy]-1-ethanol.

[0543] Et₃SiH (4.0 mL. 25.0 mmol) was added to a solution of the productof Example 108. Step 1 (1.33 g, 8.00 mmol) in MeOH (14 mL). The mixturewas cooled to 0° C., and concentrated H₂SO₄ (1.5 mL) was added dropwiseover 1.5 min. The reaction mixture was stirred at room temperature for4.5 h. More Et₃SiH (1.5 mL, 9.4 mmol) was added, and the stirring wascontinued for 1 h. After solvent removal in vacuo. H₂O was added to theresidue and pH was adjusted to pH 4 by addition of 2 M aqueous NaOH. Theaqueous solution was extracted with CH₂Cl₂ (×3). The combined organicphases were washed with brine, dried (MgSO₄) and concentrated to give anoil (1.8 g). NMR analysis of the crude product showed only 40%conversion. Therefore, the procedure was repeated by treating theresidue with Et₃SiH (3 mL), MeOH (8 mL) and concentrated H₂SO₄ (1.2 mL).After being stirred for 4 h at room temperature more H₂SO₄ (1.2 mL) wasadded. The stirring was continued for a further hour and worked up asabove. The crude product was purified by column chromatography on silica[gradient 100% isohexane to isohexane/EtOAc (1:1)] to give the titlecompound as a colorless oil. Yield 0.98 g (67%); MS m/z 182 (M)⁺. Anal.(C₁₀H₁₄O₃.0.1H₂O) C, H.

[0544] Step 2:2-{2-[3-(Methoxymethyl)phenoxy]ethoxy}-3-(1-piperazinyl)pyrazine,Maleate.

[0545] Yield of free base of the title compound 0.61 g (80%). Part ofthis material was converted to the maleate salt: mp 114-115° C.; MS m/z345 (M+H)⁺. Anal. (C₁₈H₂₄N₄O₃.C₄H₄O₄) C, H, N.

Example 110

[0546] 3-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)benzamide,Maleate.

[0547] Step 1: 3-(2-Hydroxyethoxy)benzamide.*

[0548] The title compound was prepared according to the proceduredescribed in Example 91, Step 1, starting from 3-hydroxybenzamide. Yield62%; MS m/z 181 (M)⁺. HRMS m/z calcd for C₉H₁₂NO₃ (M)⁺ 181.0739, found181.0739.

[0549] Step) 2: 3-(2-[{3-(1-piperazinyl)-2-1)pyrazinyl]oxy}ethoxy)benzamide, Maleate.

[0550] Yield of free base of the title compound 43%. The maleate saltwas prepared: mp 134-137° C.; MS m/z 344 (M+H)⁺. Anal. (C₁₇H₂₁N₅O₃C₄H₄O₄) C, H, N.

Example 111

[0551] N-Phenyl-4-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxyethoxy)aniline,Maleate.

[0552] Step 1: 2-(4-Anilinophenoxy)ethanol.*

[0553] The title product was prepared according to the proceduredescribed in Example 91, Step 1, starting from 4-anilinophenol. Solid;yield 0.85 g (75%); MS m/z 229 (M)⁺. Anal. (C₁₄H₁₅NO₂) C, H, N.

[0554] Step 2:N-Phenyl-4-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)aniline,Maleate.

[0555] Yield of free base of the title compound 44%. The maleate saltwas prepared: mp 132-133° C.; MS m/z 392 (M+H)⁺. Anal.(C₂₂H₂₅N₅O₂.C₄H₄O₄) C, H, N.

Example 112

[0556] Step 1: N-[4-(2-Hydroxyethoxy)phenyl]acetamide.*

[0557] The title product was prepared according to the proceduredescribed in Example 91, Step 1, starting from 4-acetamidophenol. Solid;yield 1.38 g (52%); MS “7/z 195 (M)⁺. Anal. (C₁₀H₁₃NO₃.0.1H₂O)C, H, N.

[0558] Step 2:N-[4-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)phenyl]acetamide.

[0559] Solid; yield 0.47 g (53%); MS m/z 357 (M)⁺. HRMS m/z calcd forC₁₈H₂₃N₅O₃ (M)⁺ 357.1801, found 357.1810.

Example 113

[0560]2-(1-piperazinyl)-3-{2-[3-(trifluoromethoxy)phenoxy]ethoxy}pyrazine,Maleate.

[0561] Step 1: 2-[3-(Trifluoromethoxy)phenoxy]ethanol.

[0562] The title product vas prepared according to the proceduredescribed in Example 91, Step 1, starting from 3-trifluoromethoxyphenol.Oil: yield 0.75 g (60%): MS m/z 222 (M)⁺. Anal. (C₉H₉F₃O₃) C, H.

[0563] Step 2:2-(1-piperazinyl)-3-{2-[3-(trifluoromethoxy)phenoxy]ethoxy}pyrazine,Maleate.

[0564] Yield of free base of the title compound 61%. The maleate saltwas prepared: mp 150-152° C.; MS m/z 326 (M+H)⁺. Anal.(C₁₇H₁₉N₅O₂*C₄H₄O₄) C, H, N.

Example 114

[0565] 2-[2-(3,5-Difluorophenoxy)ethoxy]-3-(1-piperazinyl)pyrazine,p-Toluenesulfonate.

[0566] Step 1: 2-(3,5-Difluorophenoxy)-1-ethanol. In a sealed Pyrextube, a mixture of 3,5-difluorophenol (2.19 g, 16.8 mmol), ethylenecarbonate (1.0 g, 11.4 mmol), a catalytic amount of NaH (60% in mineraloil) in DMF (1 mL) was reacted in a Labwell MW-10 microwave reactor at50W for 3 min. The reaction mixture was diluted with toluene and washedwith 5% aqueous NaOH. The organic phase was dried (MgSO₄) andconcentrated. This gave 1.59 g (80%) of the title compound as a lightred oil. MS m/z 174 (M)⁺.

[0567] Step 2:2-[2-(3,5-Difluorophenoxy)ethoxy]-3-(1-piperazinyl)pyrazine,p-Toluenesulfonate.

[0568] Yield 14%; mp 118-119° C. Anal. (C₁₆H₁₈F₂N₄O₂ C₇H₈O₃S)C, H, N.

Example 115

[0569] 2-[2-(1,3-Benzodioxol-5-yloxy)ethoxy]-3-(1-piperazinyl)pyrazine.

[0570] Step 1: 2-(1,3-Benzodioxol-5-yloxy)ethanol.*

[0571] The title compund was prepared according to the procedure ofExample 114., Step I starting from sesamol (2.0 g, 14.5 mmol) andethylene carbonate (1.0 e. 11.4 mmol): solid, yield 99%. MS m}l 182 (M).

[0572] Step 2:2-[2-(1,3-Benzodixol-5-yloxy)ethoxy]-3-(1-piperazinyl)pyrazine.

[0573] Solid: yield 71%. MS m/z 345 (M+H)⁺. Anal. (C₁₇H₂₀N₄O₄) C, H, N.

Example 116

[0574] 2-[2-(3-Butoxyphenoxy)ethoxy]-3-(1-piperazinyl)pyrazine, Maleate.

[0575] Step 1: 2-(3-Butoxyphenoxy)ethanol.

[0576] The title compund was prepared according to the procedure ofExample 114, Step 1 starting from 3-n-butoxyphenol (2.0 g, 12 mmol) andethylene carbonate (0.88 g, 10 mmol). Oil; yield 85%. MS m/z 210 (M)⁺.

[0577] Step 2: 2-[2-(3-Butoxyphenoxy)ethoxy]-3-(1-piperazinyl)pyrazine,Maleate.

[0578] Yield of free base of the title compound 77%. Part of the freebase was converted to the maleate salt. MS m/z 373 (M+H)⁺. Anal.(C₂₀H₂₈N₄O₃ C₄H₄O₄) C, H, N.

Example 117

[0579] 2-[2-(3-Trifluoromethylphenoxy)ethoxy]-3-(1-piperazinyl)pyrazine.

[0580] Step 1: 2-(3-Trifluoromethylphenoxy)ethanol.

[0581] The title compound was prepared according to the procedure ofExample 114, Step 1 starting from 3-trifluoromethylphenol (3.89 g, 24mmol) and ethylene carbonate (1.76 g, 20 mmol) with the exception thatno DMF was used. Oil; yield 64%. MS m/z 206 (M)⁺.

[0582] Step 2:2-[2-(3-Trifluoromethylphenoxy)ethoxy]-3-(1-piperazinyl)pyrazine,Maleate.

[0583] Yield of free base of the title compound 65%. Part of the freebase was converted to the maleate salt. MS m/369 (M+H)⁺. HRMS m/z calcdfor C₁₇H₁₉F₃N₄O₂ (M)⁺ 368.1460, found 368.1460.

Example 118

[0584] 2-[2-([1,1′-Biplienyl]-3-yloxy)ethoxy]-3-(1-piperazinyl)pyrazine,Maleate.

[0585] Step 1: 2-(3-Phenylphenoxy)ethanol.*

[0586] The title compund was prepared according to the procedure ofExample 114, Step 1 starting from 3-phenylphenol (1.72 g, 10.1 mmol) andethylene carbonate (0.80 g, 9.1 mmol) and DMF (3 mL). Semi-solid; yield86%. MS m/z 214 (M)⁺.

[0587] Step 2:2-[2-([1,1′-Biphenyl]-3-yloxy)ethoxy]-3-(1-piperazinyl)pyrazine,Maleate.

[0588] Yield of free base 70%. Part of the free base was converted tothe maleate salt. MS m/z 377 (M+H)⁺. Anal. (C₂₂H₂₄N₄O₂.C₄H₄O₄) C, H, N.

Example 119

[0589] 2-[2-(3-Acetamidophenoxy)ethoxy]-3-(1-piperazinyl)pyrazine,Maleate.

[0590] Step 1: 2-(3-Acetamidophenoxy)-1-ethanol*.

[0591] The title product was prepared according to the proceduredescribed in Example 114, Step 1, starting from 3-acetamidophenol (2.10g, 13.9 mmol) and ethylene carbonate (0.88 g, 10 mmol). The crudeproduct was purified by column chromatography on silica usingtoluene/EtOAc/MeOH (49:49:2). Oil; yield 99%. MS m/z 195 (M)⁺.

[0592] Step 2:2-[2-(3-Acetamidophenoxy)ethoxy]-3-(1-piperazinyl)pyrazine, Maleate.

[0593] Yield 38%; mp 154-155° C. Anal. (C₁₈H₂₃N₅O₃.C₄H₄O₄) C, H, N.

Example 120

[0594]2-[4-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)phenoxy]ethanol,Maleate.

[0595] The title product was prepared from1,4-bis(2-hydroxyethoxy)benzene. Yield of free base of the titlecompound 51%. The maleate salt was prepared: mp 127-129° C. MS m/z 361(M+H). Anal. (C₁₈H₂₄N₄O₄.C₄H₄O₄) C, H, N.

Example 121

[0596]2-[3-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxyethoxy)phenoxy]ethanol,Maleate.

[0597] The title product wasp prepared from1,3-bis(2-hydroxyethoxy)benzene. Yield of free base of the titlecompound 45%. The maleate salt as prepared: mp 111-114° C.; MS m/z 361(M+H)⁺. Anal. (C₁₈H₂₄N₄O₄.C₄H₄O₄.0.1H₂O) C, H, N.

Example 122

[0598] 2-(Benzofuran-2-ylmethoxy)-3-(1-piperazinyl)pyrazine,Hydrochloride.*

[0599] Yield 44%; mp 160-161° C. Anal. (C₁₇H₁₈N₄O₂ HCl) C, H, N.

Example 123

[0600]2-(2,3-Dihydrobenzofuranyl-2-ylmethoxy)-3-(1-piperazinyl)pyrazine,Dihydrochloride.

[0601] Yield 33%; mp 172-174° C. Anal. (C₁₇H₂₀N₄O₂.2HCl) C, H, N.

[0602] The starting material 2,3-dihydrobenzofuran-2-ylmethanol* wasobtained from benzofuran-2-carboxaldehyde by reduction with sodiumborohydride and subsequent catalytic hydrogenation.

Example 124

[0603] 2-(1-piperazinyl)-3-(tetrahydro-2-furanylmethoxy)pyrazine,Hydrochloride.

[0604] The title compound was prepared starting from tetrahydrofurfurylalcohol. Yield 65%; mp 130-136° C. Anal. (C₁₃H₂₀N₄O₂ HCl H₂O)C, H, N.

Example 125

[0605] 2-(1-piperazinyl)-3-[3-(2-pyridinyl)propoxy]pyrazine, Maleate.

[0606] The title compound was prepared starting from 2-pyridinepropanol.Yield 51%; mp 147-148° C. Anal. (C₁₆H₂₁N₅O.1.05 C₄H₄O₄) C, H, N.

Example 126

[0607] 2-(1-piperazinyl)-3-[3-(3-pyridinyl)propoxy]pyrazine, Maleate.

[0608] The title compound as prepared starting from 3-pyridinepropanol.

[0609] Yield 43%; mp 128-1130° C. Anal. (C₁₆H₂₁N₅O.C₄C₄H₄O₄) C, H, N.

Example 127

[0610] 2-(1-piperazinyl)-3-[3-(4-pyridinyl)propoxy]pyrazine, Maleate.

[0611] The title compound was prepared starting from 4-pyridinepropanol.

[0612] Yield 41%; mp 90-91° C. Anal. (C₁₆H₂₁N₅O.C₄H₄O₄.0.7H₂O)C, H, N.

Example 128

[0613] 2-[3-(6-Methyl-2-pyridinyl)propoxy]-3-(1-piperazinyl)pyrazine,Maleate.

[0614] The title compound was prepared starting from6-methyl-2-pyridinepropanol.

[0615] Yield 30%; mp 134-136° C. Anal. (C₁₇H₂₃N₅O.C₄H₄O₄) C, H, N.

Example 129

[0616] 2-[(E)-3-Phenyl-2-propenyloxy]-3-(1-piperazinyl)pyrazine.

[0617] The title compound was prepared starting from cinnamyl alcohol.Oil; yield 39%. Anal. (C₁₇H₂₀N₄O.0.2H₂O)C, H, N.

Example 130

[0618]2-(3,4-Dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-(1-piperazinyl)pyrazine,Dihydrochloride. Yield 22%; mp 171-175° C. Anal. (C₁₇H₂₁N₅O₅.2HCl) C, H,N.

Example 131

[0619]2-(4-Methyl-3,4-dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-(1-piperazinyl)-pyrazine,Hydrochloride.*

[0620] Yield 49%; mp 119° C. (dec) Anal. (C₁₈H₂₃N₅O₂.1.33 HCl) C, H, N.

Example 132

[0621]2-(2,3-Dihydro-1,4-benzoxathiin-2-ylmethoxy)-3-(1-piperazinyl)pyrazine,Fumarate.*

[0622] Yield 41%; mp 178-79° C. Anal. (C₁₇H₂₀N₄O₂S.C₄H₄O₄) C, H, N.

Example 133

[0623] 2-(3,4-Dihydro-2H-chromen-2-ylmethoxy)-3-(1-piperazinyl)pyrazine,Hydrochloride.*

[0624] Yield 45%; mp 170-175° C. Anal. (C₁₈H₂₃N₄O₂ HCl) C, H, N.

Example 134

[0625] 2-(5-Isoquinolinyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether,Maleate.

[0626] Step 1: 2-(5-Isoquinolinyloxy)ethanol.

[0627] A mixture of 5-hydroxyisoquinoline (2.05 g, 14.1 mmol), ethylenecarbonate (1.43 g, 16.2 mmol), K₂CO₃ (0.97 g, 7.1 mmol) in DMF (6 mL)was heated at 155° C. for 1.5 h under stirring in a sealed tube. Aftercooling, the mixture was diluted with CHCl₃ and filtered through a padof Celite. The brownish filtrate was concentrated in vacuo, and theresidue was purified by chromatography on silica gel using EtOAc aseluent to give 1.8 g (67%) of the title product as a beige oil whichsolidified on standing: mp 64-67° C.; HRMS m/z calcd for C₁₁H₁₁NO₂ (M)⁺189.0790, found 189.0789. Anal. (C₁₁H₁₁NO₂) C, H, N.

[0628] Step 2: 2-(5-Isoquinolinyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether, Maleate.

[0629] Yield 55% as the free base. The free base was converted to themaleate salt: nip 178-180.5° C.; HRMS m/z calcd for C₁₉H₂₁N₅O₂ (M)⁺351.1695, found 351.1694. Anal. (C₉H₂₁N₅O₂.C₄H₄O₄) C, H, N.

Example 135

[0630] 2-(5-Quinolinyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether,Maleate.

[0631] Step 1: 2-(5-Quinolinyloxy)ethanol

[0632] The title compound was prepared according to the proceduredescribed in Example 134, Step 1, starting from 5-hydroxyquinoline (0.93g, 6.40 mmol). Yield 1.19 g (91%); mp 109-111° C.; HRMS m/z calcd forC₁₁H₁₁NO₂ (M) 189.0790, found 1.89.0786. Anal. (C₁₁H₁₁NO₂) C, H, N.

[0633] Step 2: 2-(5-Quinolinyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether, Maleate.

[0634] Yield 61% as the free base. The free base was converted to themaleate salt: mp 132-135° C.; HRMS m/z calcd for C₁₉H₂₁N₅O₂ (M)⁺351.1695, found 351.1681. Anal. (C₁₉H₂₁N₅O₂.1.8C₄H₄O₄) C, H, N.

Example 136

[0635] 2-(6-Quinolinyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether,Maleate.

[0636] Step 1: 2-(6-Quinolinyloxy)ethanol.

[0637] The title compound was prepared according to the proceduredescribed in Example 91, Step 1, starting from 6-hydroxyquinoline. Yield78%; mp 68-70° C. Anal. (C₁₁H₁₁NO₂) C, H, N.

[0638] Step 2: 2-(6-Quinolinyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether, Maleate.

[0639] Yield 33%; mp 167-169° C. Anal. (C₁₉H₂₁N₅O₂.C₄H₄O₄) C, H, N.

Example 137

[0640] 2-(7-Quinolinyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether,Maleate.

[0641] Step 1: 2-(7-Quinolinyloxy)ethanol.

[0642] The title compound was prepared according to the proceduredescribed in Example 91. Step 1, starting from 7-hydroxyquinoline. Yield76%; mp 93-950C. Anal. (C₁₁H₁₁NO₂) C, H, N.

[0643] Step 2: 2-(7-Quinolinyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether, Maleate.

[0644] Yield 39%: mp 156-158° C. Anal. (C₁₉H₂₁N₅O₂.C₄H₄O₄) C, H, N.

Example 138

[0645] 2-(8-Quinolinyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether.

[0646] Step 1: 2-(8-Quinolinyloxy)ethanol.*

[0647] The title compound was prepared according to the proceduredescribed in Example 91, Step 1, starting from 8-hydroxyquinoline. Yield48%; mp 82-84° C. Anal. (C₁₁H₁₁NO₂) C, H, N.

[0648] Step 2: 2-(8-Quinolinyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether.

[0649] Yield 62%; mp 98-100° C. Anal. (C₉₁H₂₁N₅O₂.0.05 EtOAc) C, H, N.

Example 139

[0650]5-Chloro-8-(2-([3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-2-quinolinamine,Fumarate.

[0651] Step 1: 2-[(5-Chloro-8-quinolinyl)oxy]-1-ethanol.

[0652] The title compound was prepared according to the proceduredescribed in Example 91, Step 1, starting from5-chloro-8-hydroxyquinoline (3.59 g, 20 mmol). Yield 48%. Pos-EI-MSshows M⁺ and 5 ions supporting the stated structure; HRMS m/z calcd forC₁₁H₁₀ClNO₂ (M)⁺ 223.0400, found 223.0392. Anal. (C₁₁H₁₀ClNO₂) C, H, N.

[0653] Step 2:5-Chloro-8-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-2-quinolinamine,Fumarate.

[0654] The crude product was purified by column chromatography on silicausing CHCl₃/MeOH/NH₄OH (90:10:0.3) as eluent. After evaporation ofsolvents from the combined pure fractions, the resulting free base wasconverted to its fumaric acid salt. Recrystallization from waterafforded 1.22 g (50%) of the title product as white crystals: mp 178° C.(dec). Anal. (C₁₉H₂₀N₅O₂.C₄H₄O₄) C, H, N.

Example 140

[0655] 2-(Benzofuran-7-yloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether,Maleate.

[0656] Step) 1: 2-(Benzofuran-7-yloxy)ethanol.

[0657] The title compound was prepared according to the proceduredescribed in Example 91, Step 1, starting from 7-hydroxybenzofuran* andwas isolated as a semi-solid; yield 79%.

[0658] Step 2: 2-(Benzofuran-7-yloxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether, Maleate.

[0659] Yield 42% as the free base. A portion of the free base wasconverted to the maleate salt: mp 177-179° C.; MS m/z 341 (M+H)⁺. Anal.(C₁₈H₂₀N₄O₃.C₄H₄O₄) C, H, N.

Example 141

[0660] 7-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-1H-indole.

[0661] Step 1: 2-(1H-Indol-7-yloxy)-1-ethanol.

[0662] A mixture of 7-hydroxyindole (1.00 g, 7.51 mmol) and ethyleneoxide (0.33 g, 7.50 mmol) in dioxane (3 mL) was placed in a reactiontube. NaH (60% in oil; 0.100 g, 2.45 mmol) was added and the reactionmixture was stirred at 100° C. for 5 days. The reaction mixture waspoured into water, extracted with EtOAc, dried (MgSO₄) and concentrated.The residue was purified by chromatography on silica gel usingtoluene/EtOAc (1:1) as eluent to give 0.45 g (34%) of the title product.Pos-EI-MS shows M⁺ and 5 ions supporting the stated structure. HRMS m/zcalcd for C₁₀H₁₁NO₂ (M)⁺ 177.0790, found 177.0799.

[0663] Step 2:7-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-1H-indole

[0664] The product obtained in Step 1 above (0.200 g, 1.13 mmol) anddioxane (4 mL) was placed in a reaction tube and NaH (60% in oil; 0.060g, 1.50 mmol) was added. When the gas evolution had ceased,2-chloro-3-(1-piperazinyl)pyrazine (0.228 g, 1.15 mmol; from Example 90,Step 1) was added and the tube sealed. The mixture %%,as stirred at 100°C. for 3 h. After cooling, the reaction mixture was poured into waterand extracted with EtOAc. The organic layer was extracted with 0.5 Maqueous HCl. The pH of the aqueous phase was adjusted to pH 11 with NaOHand extracted with EtOAc. The organic layer was dried (MgSO₄) andconcentrated to give 0.31 g (81%) of the title product. Pos-EI-MS showsM⁺ and 9 ions supporting the stated structure. HRMS m/z calcd forC₁₈H₂₁N₅O₂ (M)⁻ 339.1695, found 339.1696.

Example 142

[0665] 6-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-1H-indole.

[0666] Step 1: 21H-Indol-6-yloxy)-1-ethanol.

[0667] A mixture of 6-hydroxyindole (2.66 g, 20 mmol) and K₂CO₃ (3.04 g,22 mmol) was stirred in DMF (10 mL) at 80° C. for 10 min. A solution ofethylene carbonate (1.94 g, 22 mmol) in DMF (4 mL) was added and themixture was heated at 125° C. for 3 h. The mixture was concentrated,diluted with water, and extracted with toluene. The organic phase waswashed with 1 M aqueous Na₂CO₃ and brine. The organic layer was dried(Na₂SO₄) and concentrated. The residue was purified by flashchromatography on silica using EtOAc/toluene (1:4→36:65) as eluent.Yield 1.02 g (29%); mp 74-77° C.; HRMS m/z calcd for C₁₀H₁₁NO₂ (M)⁺177.0790, found 177.0784. Anal. (C₁₀H₁₁NO₂) C, H, N.

[0668] Step 2:6-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-1H-indole.

[0669] Yield 59%; mp 111-113° C.; MS-EI m/z 339 (M)⁺. Anal. (C₁₈H₂₁N₅O₂)C, H, N.

Example 143

[0670]2-Methyl-5-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-1,3-benzothiazole,Hydrochloride.

[0671] Step 1: 2-[(2-Methyl-1,3-benzothiazol-5-yl)oxy]ethanol.

[0672] The title compound was prepared according to the proceduredescribed in Example 91, Step 1, starting from2-methyl-1,3-benzothiazol-5-ol. Yield 61%; mp 67-68° C. HRMS m/z calcdfor C₁₀H₁₁NO₂S (M)⁺ 209.0510, found 209.0502. Anal. (C₁₀H₁₁NO₂S) C, H,N.

[0673] Step 2:2-Methyl-5-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-1,3-benzothiazole,Hydrochloride.

[0674] Yield 58%; mp 188-190° C. HRMS m/z calcd for C₁₈H₂₁N₅O₂S (M)⁺371.1416, found 371.1421. Anal. (C₁₈H₂₁N₅O₂S HCl.0.3H₂O) C, H, N.

Example 144

[0675] 2-[2-(2-Methoxy-5-methylphenoxy)ethoxy-3-(1-piperazinyl)pyrazine, Maleate.

[0676] Step 1: 2-(2-Methoxy-5-methylphenoxy)ethanol.

[0677] The title compound was prepared according to the proceduredescribed in Example 91, Step 1, starting from 2-methoxy-5-methylphenol.Yield 56%; mp 42-43° C. Anal. (C₁₀H₁₄O₃) C, H.

[0678] Step 2:2-[2-(2-Methoxy-5-methylphenoxy)ethoxy]-3-(1-piperazinyl)pyrazine,Maleate.

[0679] Yield 56%; mp 148-149° C. Anal. (C 18H₂₄N₄O₃ C₄H₄O₄). C, H, N.

Example 145

[0680] 7-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-1-naphthylamine,Maleate.

[0681] Step 1: 2-[(8-Amino-2-naphthyl)oxy]ethanol, Hydrochloride.

[0682] The title compound was prepared according to the proceduredescribed in Example 91, Step 1, starting from 8-amino-2-naphthol. Yield40%; mp 185° C. (dec). Anal. (C₁₂H₁₃NO₂.HCl) C, H, N.

[0683] Step 2:7-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-1-naphthylamine,Maleate.

[0684] Yield 21%; mp 120° C. (dec). Anal. (C₂₀H₂₃N₅O₂.1.7C₄H₄O₄) C, H,N.

Example 146

[0685]2-(7-Nitro-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)-3-(1-piperazinyl)pyrazine.

[0686] Step 1: 7-Nitro-2-hydroxymethyl-2,3-dihydro-1,4-benzodioxine.

[0687] Trifluoroacetic anhydride (20 mL, 149 mmol) was added dropwise tosolution of 2-hydroxymethyl-2,3-dihydro-1,4-benzodioxine (6.64 g. 40mmol) and NH₄NO₃ (84.8 g 60 mmol) in CH₂Cl₂ (300 mL). The reactionmixture was stirred at room temperature for 4 h and then concentratedunder reduced pressure. The residue was purified by chromatography onsilica gel using EtOAc/isohexane (1:3 to 2:3) as eluent to give a smallfraction (0.3 g, 4%) of the pure title compound and 6.5 g of a mixtureof the C6- and C7 regioisomeric nitro derivatives. The regioisomericmixture was taken on to Example 147 Step 1, without separation.

[0688] Step 2:2-(7-Nitro-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)-3-(1-piperazinyl)pyrazine.

[0689] The title compound was prepared starting from the pure productobtained in Step 1 above. Oil; yield 43%; mp 133-135° C. HRMS m/z calcdfor C₁₇H₁₉N₅O₅ (M)⁺ 373.1386, found 373.1367.

Example 147

[0690]2-(7-Acetamido-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)-3-(1-piperazinyl)pyrazine.

[0691] Step 1: 7-Amino-2-hydroxymethyl-2,3-dihydro-1,4-benzodioxine.

[0692] A mixture of 6- and7-nitro-2-hydroxymethyl-2,3-dihydro-1,4-benzodioxine (6.3 g, 30 mmol;from Example 146, Step 1), ammonium formate (2.8 g, 45 mmol), and 10%Pd/C (0.4 g) in MeOH (200 mL) was stirred at room temperature for 3 h.The reaction mixture was filtered through a pad of Celite. The pad waswashed with several portions of MeOH and the filtrate was concentratedin vacuo. The mixture of 6- and 7-aminosubstituted-2,3-dihydro-1,4-benzodioxin derivatives was separated bychromatography on silica gel using EtOAc/isohexane (1:3 to 2:3) aseluent to give 2.8 g (58%) of the title product as an oil which was useddirectly in the next step.

[0693] Step 2: 7-Acetamido-2-hydroxymethyl-2,3-dihydro-1,4-benzodioxine.

[0694] Acetic anhydride (0.24 g, 2.4 mmol) was added to a stirredmixture of the title compound from Step 1 above (0.30 g, 1.66 mmol) andEt₃N (0.70 g, 6.9 mmol) in CH₂Cl₂ (30 mL). The reaction was stirred atroom temperature for 15 h. More acetic anhydride (0.10 g, 1.0 mmol) wasadded and the mixture was stirred for a further 5 h at room temperature.The mixture was concentrated and the residue purified by chromatographyon silica gel using EtOAc/isohexane (1:3 to 2:3) as eluent to give 170mg (46%) of the title product as an oil.

[0695] Step 3:2-(7-Acetamido-2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)-3-(1-piperazinyl)pyrazine.

[0696] Oil; yield 45%. HRMS m/z calcd for C₁₉H₂₃N₅O₄ (M)⁺ 385.1750,found 385.1741.

Example 148

[0697]2-[(2S)-2,3-Dihydro-1,4-benzodioxin-2-ylmetlloxy]-3-(1-piperazinyl)pyrazine,Hydrochloride.*

[0698] Mp 160° C. (dec). Anal. (C₁₇H₂₀N₄O₃ HCl) C, H, N.

Example 149

[0699]2-[(2R)-2,3-Dihydro-1,4-benzodioxin-2-ylmethoxy]-3-(1-piperazinyl)pyrazine,Hydrochloride.*

[0700] Mp 165° C. (dec). Anal. (C₁₇H₂₀N₄O₃.HCl) C, H, N.

Example 150

[0701] 2-(3-Pyridyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether,Hydrochloride.

[0702] Step 1: 2-(3-Pyridyloxy)ethanol.*

[0703] A mixture of 3-hydroxypyridine (2.00 g., 21 mmol),2-chloroethanol (1.69 g. 21 mmol) and K₂CO₃ (8.7 g, 63 mmol) in DMF (10mL) was stirred at 130° C. for 3 h. After cooling, the black mixture wasfiltered through a short bed of alumina using acetone as eluent toafford a brown oil which was partitioned between water (30 mL) andCH₂Cl₂ (40 mL). The aqueous phase was extracted with CH₂Cl₂ (3×40 mL),and the combined organic extracts were dried over MgSO₄ and filtered.The filtrate was concentrated to give 0.55 g (19%) of the title compoundas a light brown oil. Anal. (C₇H₉NO₂.0.2 H₂O)C, H, N.

[0704] Step 2: 2-(3-Pyridyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether, Hydrochloride.

[0705] Yield 41%; mp 170-175° C. Anal. (C₁₅H₁₉N₅O₂.2 HCl 2H₂O) C, H, N.

Example 151

[0706] 2-(4-Pyridyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether,Hydrochloride.

[0707] Step 1: 2-(4-Pyridyloxy)ethanol.*

[0708] The title compound was prepared according to the proceduredescribed in Example 150, Step 1. Yield 19%; mp 119-121° C. Anal.(C₇H₉NO₂) C, H, N.

[0709] Step 2: 2-(4-Pyridyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether, Hydrochloride.

[0710] Yield 58%; mp 170° C. (dec). Anal. (C₁₅H₁₉N₅O₂.2 HCl 2H₂O)C, H,N.

Example 152

[0711] 2-(2-Pyridyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether,Maleate.

[0712] Step 1: 2-(2-Pyridyloxy)ethanol, Hydrochloride.*

[0713] A mixture of ethylene carbonate (2.78 g, 31.5 mmol),2-hydroxypyridine (3.00 g, 31.5 mmol) and potassium carbonate (4.36 g,31.5 mmol) in DMF (50 mL) was heated at 150° C. for 1 h. After cooling,the reaction mixture was concentrated in vacuo. The residue wasdissolved in water (5 mL) and applied to a column with hydromatrixmaterial. The column was eluted with EtOAc. The elute was concentratedand the remaining oil was purified by silica gel chromatography usingisohexane/EtOAc (6:4) as eluent. This furnished the free base of thetitle compound as an oil which was converted to the hydrochloride salt:yield 10.00 g (18%); mp 97-98° C. Anal. (C₇H₉NO₂.HCl) C, H, N.

[0714] Step 2: 2-(2-Pyridyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether, Maleate.

[0715] Yield 27%: mp 130-132° C. Anal. (C₁₅H₁₉N₅O₂.C₄C₄O₄) C, H, N.

Example 153

[0716] 2-(6-Methyl-3-pyridyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether, Hydrochloride.

[0717] Step 1: 2-(6-Methyl-3-pyridyloxy)ethanol.

[0718] The title compound was prepared according to the proceduredescribed in Example 91, Step 1, starting from3-hydroxy-6-methylpyridine. Yield 25%; mp 49-51° C. Anal. (C₈H₁₁NO₂) C,H, N.

[0719] Step 2: 2-(6-Methyl-3-pyridyloxy)ethyl3-(1-piperazinyl)-2-pyrazinyl ether, Hydrochloride.

[0720] Yield 50%; mp 157° C. (dec). Anal. (C₁₆H₂₁N₅O₂ 2.3 HCl 0.2 Et₂O)C, H, N.

Example 154

[0721] 2-(2-Methyl-3-pyridyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether, Hydrochloride.

[0722] Step 1: 2-(2-Methyl-3-pyridyloxy)ethanol.

[0723] The title compound was prepared according to the proceduredescribed in Example 150, Step 1, starting from3-hydroxy-2-methylpyridine. Yield 36%; mp 75-80° C. Anal. (C₈H₁₁NO₂) C,H, N.

[0724] Step 2: 2-(2-Methyl-3-pyridyloxy)ethyl3-(1-piperazinyl)-2-pyrazinyl ether, Hydrochloride.

[0725] Yield 36%; mp 50° C. (dec). Anal. (C₁₆H₂₁N₅O₂ 3.1 HCl 0.2 Et₂O)C,H, N.

Example 155

[0726] 2-(5-Chloro-3-pyridyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether, Hydrochloride.

[0727] Step 1: 2-(5-Chloro-3-pyridyloxy)ethanol.

[0728] The title compound was prepared according to the proceduredescribed in Example 150, Step 1, starting from 5-chloro-3-pyridinol.Yield 25%; mp 38-40° C. HRMS m/z calcd for C₇H₈ClNO₂ (M)⁺ 173.0244,found 173.0244.

[0729] Step 2: 2-(5-Chloro-3-pyridyloxy)ethyl3-(1-piperazinyl)-2-pyrazinyl ether, Hydrochloride.

[0730] Yield 65%; mp 104° C. (dec). Anal. (C₁₅H₁₈ClN₅O₂.1.9 HCl.0.3Et₂O) C, H, N.

Example 156

[0731] 2-[2-(1-Benzothien-3-yloxy)ethoxy]-3-(1-piperazinyl)pyrazine,Maleate.

[0732] Step 1: 2-(1-Benzothien-3-yloxy)ethanol.

[0733] A mixture of 3-bromobenzothiophene (3.00 g, 14.1 mmol), KO-t-Bu(4.74 g, 42.2 mmol), copper (II) oxide (0.56 g, 7.0 mmol) and potassiumiodide (2.34 g, 14.1 mmol) in ethylene glycol (10 mL) was stirred at140° C. for 24 h. The reaction was quenched with water (100 mL) andfiltered through a pad of Celite. The water phase was extracted withEtOAc (3×50 mL). The organic phase was treated with MgSO₄ and silica,filtered through Celite and concentrated. The remaining oil was purifiedby column chromatography on silica using isohexane/EtOAc (6:4) aseluent. The product crystallized on standing to give 1.63 g (60%) of thetitle product: mp 55-56° C. Anal. (C₁₀H₁₀O₂S) C, H.

[0734] Step 2:2-[2-(1-Benzothien-3-yloxy)ethoxy]-3-(1-piperazinyl)pyrazine, Maleate.

[0735] Solid; yield 0.23 g (32%); mp 147-1490C. Anal. (C₁₈H₂₀N₄O₂SC₄H₄O₄) C, H, N.

Example 157

[0736] 2-(3-Thienyloxy)ethyl 3-(1-piperazinyl)-2-pyrazinyl ether,Dihydrochloride.*

[0737] Yield 39%; mp 75-85° C. Anal. (C₁₄H₁₈N₄O₂S 2.1 HCl) C, H, N.

Example 158

[0738] 2-(2,3-Dihydro-2,2-dimethyl-7-benzofuranyloxy)ethyl3-(1-piperazinyl)-2-pyrizinyl ether, Maleate.

[0739] A mixture of 2,3-dihydro-2,2-dimethyl-7-benzofuranol (0.82 g, 5.0mmol), ethylene oxide (0.22 g, 5.0 mmol), triethylamine (3 drops) anddioxane (4 mL) was heated at 100° C. in a sealed tube for 3 d. Thesolution was cooled in an ice-bath and KO-t-Bu (0.56 g 5 mmol) followedby 2-chloro-3-(1-piperazinyl)pyrazine (0.79 g, 4.0 mmol; from Example90, Step 1) were added. The mixture was stirred at room temperature for30 min and at 100° C. for 4 h, allowed to cool, diluted with CH₂Cl₂ andfiltered. The filtrate was concentrated and purified by chromatographyon silica gel (gradient: PhMe to PhMe/MeOH/Et₃N, 8:1:1) to give 1.46 gof a beige viscous oil. Maleic acid (0.46 g, 4.0 mmol) and dry MeOH (10mL) was added. The mixture was heated until a clear solution formed.Upon cooling, the maleate salt of the title compound crystallized as apale beige solid: yield 1.40 g (72%); mp 156-157° C. Anal. (C₂₀H₂₆N₄O₃C₄H₄O₄) C, H, N.

Example 159

[0740] 2-(1,3-Benzoxazol-4-yloxy)ethyl 3-(1-piperazinyl)-2-pyrazinylether, Maleate.

[0741] Step 1: 2-(1,3-Benzoxazol-4-yloxy)ethanol.

[0742] K₂CO₃ (254 mg, 1.84 mmol) was added to a stirred solution of4-hydroxybenzoxazole* (248 mg, 1.84 mmol) in DMF (5 mL) at roomtemperature. The mixture was heated at 90° C. for 15 min and ethylenecarbonate (176 mg, 2.00 mmol) was added. The mixture was stirred at 150°C. for 2 h and allowed to attain room temperature. The mixture wasdiluted with water (2 mL) and MeOH (2 mL), and concentrated. The residuewas partitioned between water and CH₂Cl₂. The aqueous layer wasseparated and extracted with CH₂Cl₂ (2×10 mL). The organic phases werepooled and washed with water and brine, and dried over MgSO₄. Thefiltrate was concentrated to give the product as a brown oil that slowlysolidified: yield 278 mg (84%); mp 47-49° C. Anal. (C₉H₉NO₃) C, H. N.

[0743] Step 2: 2-(1,3-Benzoxazol-4-yloxy)ethyl3-(1-piperazinyl)-2-pyrazinyl ether, Maleate.

[0744] KO-t-Bu (146 mg. 1.30 mmol) was added in one portion to a stirredsolution of 2-(1,3-benzoxazol-4-yloxy)ethanol (223 mg°. 1.24 mmol) indioxane (5 ml) at room temperature. After 15 min.2-chloro-3-(1-piperazinyl)pyrazine (247 mg, 1.24 mmol; from Example 90.Step 1) was added in one portion followed by dioxane (3 mL). The mixturewas stirred at room temperature for 10 min and at 100° C. for 3 h,allowed to cool, diluted with CH₂Cl₂ and filtered through Celite. Thefiltrate was concentrated and purified by chromatography on silica gel(gradient: PhMe to PhMe/MeOH/Et₃N, 8:1:1) to give the product (70 mg,17%) as a beige viscous oil. The maleate salt was prepared as describedin Example 158: mp 191-193° C. Anal. (C₁₇H₁₉N₅O₃ C₄H₄O₄) C, H, N.

Example 160

[0745] 4-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-2-quinolinamine,Trihydrochloride.

[0746] Step 1: 2-[(2-Amino-4-quinolinyl)oxy]-1-ethanol.

[0747] To a mixture of 2-amino-4-hydroxyquinoline (0.505 g, 3.15 mmol)and K₂CO₃ (0.87 g, 6.3 mmol) in DMF (10 mL) was added of 2-bromoethanol(0.470 g, 3.78 mmol). The mixture was stirred at 150° C. for 7 h. Thereaction mixture was concentrated and the residue purified by columnchromatography on silica using MeOH/CHCl₃ (1:9) as eluent. The resultingbrown oil (0.30 g, 30%), which was used directly in the next step,contained 75% of the desired product and 25% of unreacted startingmaterial. MS m/z 205 (M+H)⁺.

[0748] Step 2:4-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-2-quinolinamine,Trihydrochloride.

[0749] The product obtained in Step 1 (0.30 g, 1.5 mmol) was dissolvedin DMF (4 mL) and treated with NaH (55% dispersion in mineral oil; 0.12g, 3.0 mmol). After beeing stirred for 5 min at room temperature.2-chloro-3-(1-piperazinyl)pyrazine (0.212 g, 1.07 mmol; from Example 90,Step 1) was added. The reaction mixture was stirred at 70° C. for 4 hand at room temp for 14 h. Purification by column chromatography onsilica gel using 20% MeOH in CHCl₃ as eluent furnished 0.102 g (25%) ofthe free base of the title compound which % vas converted to ahydrochloric acid salt: nmp 156° C. (dec). HRMS m/z calcd for C₁₉H₂₂N₆O₀(M)⁺ 366.1804, found 366.1795.

Example 161

[0750]2-(3,4-Dihydro-2H-pyrido[3,2-b]-1,4-oxazin-2-ylmethoxy)-3-(1-piperazinyl)pyrazine,Maleate.

[0751] Step 1: 3,4-Dihydro-3-oxo-2H-pyrido[3,2-b]-1,4-oxazin-2-carboxylic acid ethyl ester.

[0752] Diethyl chloromalonate (9.73 g, 50 mmol) was added to a stirredmixture of 3-hydroxy-2-aminopyridine (5.51 g, 50 mmol), triethylamine(6.97 mL, 50 mmol) and EtOH (100 mL) at room temperature. The mixturewas heated at reflux for 17 h and allowed to attain room temperature.The precipitate formed was filtered off, washed with EtOH and dried togive the product as a white solid: yield 3.85 g (35%); mp 160-162° C.Anal. (C₁₀H₁₀N₂O₄) C, H, N.

[0753] Step 2: 3,4-Dihydro-2H-pyrido[3,2-b]-1,4-oxazin-2-ylmethanol.

[0754] A solution of3,4-dihydro-3-oxo-2H-pyrido[3,2-b]-1,4-oxazin-2-carboxylic acid ethylester (1.10 g, 5.0 mmol) in THF (50 mL) was added over 5 min to astirred mixture of LiAlH₄ (0.38 g, 10 mmol) and THF (20 mL) at 40° C.The mixture was stirred at 45° C. for 30 min and at reflux for 4 h. Themixture was allowed to attain room temperature and excess LiAlH₄decomposed with 50% aqueous NaOH. The mixture was filtered throughCelite, and the filtrate was concentrated. The residue (0.42 g) wasextracted with CH₂Cl₂ and the extract was concentrated and purified bychromatography on silica gel (gradient: PhMe to PhMe/MeOH/Et₃N, 8:1:1)to give the product as a white solid: yield 0.11 g (13%); mp 123-124° C.Anal. (C₈H₁₀N₂O₂) C, H, N.

[0755] Step 3:2-(3,4-Dihydro-2H-pyrido[3,2-b]-1,4-oxazin-2-ylmethoxy)-3-(1-piperazinyl)pyrazine,Maleate.

[0756] The title compound was prepared in an analogous manner to Example159, Step 2, starting from3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazin-2-ylmethanol and was isolated asa brownish solid. Yield 47%: mp 154-158° C. Anal. (C₁₆H₂₀N₆O₂.1.2C₄H₄O₄) C, H, N.

Example 162

[0757] 2-[2-(3-Pyridinyloxy)ethoxy]-3-(1-piperazinyl)quinoxaline,Maleate.

[0758] Step 1: 2-Chloro-3-(1-piperazinyl)quinoxaline, Maleate.*

[0759] A mixture of 2,3-dichloroquinoxaline (3.05 g. 15.3 mmol),piperazine (2.64 g, 30.6 mmol) and K₂CO₃ (2.12 g, 15.3 mmol) inacetonitrile (20 mL) was stirred at 55° C. for 1 h. The reaction mixturewas diluted with CHCl₃, filtered, and concentrated to give a yellowishsolid which was purified by chromatography on silica gel usingCHCl₃/MeOH (9:1) as eluent. The resulting solid was redissolved in CHCl₃and applied to a short (4 cm) plug of alumina. Elution with CHCl₃afforded 3.08 g (81%) of the free base of the title compound, which wasisolated as a light yellow solid. A portion of the free base wasconverted to the maleate and recrystallized from MeOH/ether: mp 165-166°C.; HRMS m/z calcd for C₁₂H₁₃ClN₄ (M)⁺ 248.0829, found 248.0830. Anal.(C₁₂H₁₃ClN₄.C₄H₄O₄) C, H, N.

[0760] Step 2:2-[2-(3-Pyridinyloxy)ethoxy]-3-(1-piperazinyl)quinoxaline, Maleate.

[0761] KO-t-Bu (0.57 g, 5.1 mmol) was added to a stirred solution of2-(3-pyridyloxy)ethanol (0.97 g, 7.0 mmol; from Example 150, Step 1) indioxane (20 mL) and the mixture was stirred for 3 min at roomtemperature. The free base from Step 1 above (0.97 g, 3.89 mmol) wasthen added and the resulting mixture was stirred at 80° C. for 4 h. Thereaction mixture was diluted with CH₂Cl₂, filtered, and concentrated togive a yellowish oil which was purified by chromatography on silica gelusing CHCl₃/MeOH (9:1) as eluent. The resulting oil was redissolved inCHCl₃ and applied to a short (4 cm) plug of alumina. Elution with CHCl₃afforded 1.20 g (88%) of the free base of the title compound as a lightbeige oil. The free base was converted to the maleate salt andrecrystallized from MeOH/ether: mp 137-139° C.; HRMS m/z calcd forC₁₉H₂₁N₅O₂ (M)⁺ 351.1695, found 351.1701. Anal. (C₁₉H₂₁N₅O₂.1.3C₄H₄O₄)C, H, N.

Example 163

[0762]2-[2-(3-Pyridinyloxy)ethoxy]-3-(1-piperazinyl)-6,7-difluoroquinoxaline,Maleate

[0763] Step 1: 2-Chloro-3-(1-piperazinyl)-6,7-difluoroquinoxaline.

[0764] Piperazine (0.86 g, 10 mmol) was added to a stirred suspension of6,7-difluoro-2,3-dichloroquinoxaline* (1.18 g, 5 mmol) in EtOH (50 mL)at room temperature. The mixture was heated at 75° C. for 17 h, allowedto cool and filtered to give the product as a pale yellow solid: yield0.40 g (28%); mp 294-297° C. (dec). MS m/z 285/287 (M+H)⁺.

[0765] Step 2:2-[2-(3-Pyridinyloxy)ethoxy]-3-(1-piperazinyl)-6,7-difluoroquinoxaline,Maleate.

[0766] The title compound was prepared according to the proceduredescribed in Example 162, Step 2, starting from2-chloro-3-(1-piperazinyl)-6,7-difluoroquinoxaline (230 mg, 0.8 mmol)and 2-(3-pyridinyloxy)ethanol (140 mg, 1 mmol; from Example 150, Step1).

[0767] Yield 95 mg (31%). The maleate salt was obtained as described inExample 158: mp 110-5° C. Anal. (C₁₉H₁₉F₂N₅O₂ 1.5 C₄H₄O₄) C, H, N.

Example 164

[0768]2-[2-(3-Pyridinyloxy)ethoxy]-3-(1-piperazinyl)-6,7-dichloroquinoxaline,Maleate.

[0769] Step 1: 3-(1-piperazinyl)-2,6,7-trichloroquinoxaline.

[0770] Piperazine (0.69 g, 8.06 mmol) was added to a stirred suspensionof 2,3,6,7-tetrachloroquinoxaline (1.08 g, 4.03 mmol) in EtOH (125 mL)at room temperature. The mixture was stirred at room temperature for 8 hand filtered to give the product as a pale yellow solid: yield 0.88 g(69%); mp>300° C. MS m/z 316/318 (M)⁺.

[0771] Step 2:2-[2-(3-Pyridinyloxy)ethoxy]-3-(1-piperazinyl)-6,7-dichloroquinoxaline,Maleate.

[0772] The title compound was prepared according to the proceduredescribed in Example 162, Step 2, starting from3-(1-piperazinyl)-2,6,7-trichloroquinoxaline (270 mg, 1.00 mmol) and2-(3-pyridinyloxy)ethanol (170 mg, 1.20 mmol; from Example 150, Step 1).Yield 135 mg (32%). The maleate salt was obtained as described inExample 158: mp 187-189° C. Anal. (C₁₉H₁₉Cl₂N₅O₂.C₄H₄O₄) C, H, N.

Example 165

[0773]2-[2-(3-Pyridinyloxy)ethoxy]-3-(1-piperazinyl)thieno[3,4-b]pyrazine,Maleate.

[0774] Step 1: 2,3-Dichlorothieno[3,4-b]pyrazine.

[0775] 1,4-Dihydro-thieno[3,4-b]pyrazine-2,3-dione* (1.26 g, 7.5 mmol)and POCl₃ (6.9 mL, 75 mmol) was stirred at reflux for 21 h. The darkmixture was poured onto ice and extracted with CH₂Cl₂ (4×30 mL). Theorganic extracts were pooled and concentrated to give 0.11 g (7%) of thetitle product which was used in the next step without purification.

[0776] Step 2: 2-Chloro-3-(1-piperazinyl)-thieno[3,4-b]pyrazine.

[0777] Piperazine (92 mg, 1.07 mmol) was added to a stirred suspensionof 2,3-dichlorothieno[3,4-b]pyrazine (110 mg, 0.54 mmol) in EtOH (5 mL)at room temperature. The mixture was stirred at reflux for 16 h andfiltered. The solid was purified by chromatography on silica gel(gradient: PhMe to PhMe/MeOH/Et₃N, 8:1:1) to give 40 mg (29%) of theproduct as an orange solid. The material was used without furtherpurification in the next step.

[0778] Step 3: 2-[2-(3-Pyridinyloxy)ethoxy]-3-(1-piperazinyl)thieno[3,4-b]pyrazine, Maleate.

[0779] The title compound was prepared according to the proceduredescribed in Example 162, Step 2, starting from2-chloro-3-(1-piperazinyl)-thieno[3,4-b]pyrazine (40 mg, 0.16 mmol; fromStep 2 above) and 2-(3-pyridinyloxy)ethanol (44 mg, 0.31 mmol; fromExample 150, Step 1. Yield 38 mg (66%). The maleate was obtained asdescribed in Example 158: mp 152-156° C. Anal. (C₁₇H₁₉N₅O₂S.1.8 C₄H₄O₄)C, H, N.

Example 166

[0780] 2-[2-(5-Pyrimidin) yloxy)ethoxy]-3-(1-piperazinyl)quinoxaline.

[0781] Step 1: 2-(5-Pyrimidinyloxy)ethanol.

[0782] KO-t-Bu (7.70 g, 68.6 mmol) was added to ethylene glycol (10.45g, 168.4 mmol) under stirring. The mixture was gently heated in order toconsume all KO-t-Bu. 5-Bromopyrimidine (8.45 g, 53.1 mmol) was added tothe light brownish mixture. After 8 h of stirring at 130° C., CH₂Cl₂ (50mL) was added to the brownish reaction mixture and two layers wereformed. The CH₂Cl₂ layer was saved and the other layer was extractedwith additional portions of CH₂Cl₂. The combined CH₂Cl₂ layers wereconcentrated in vacuo and the oily residue purified by columnchromatography on silica gel using CHCl₃/MeOH (9:1) as eluent to give0.45 g (6%) of the title product as an oil sufficiently pure for thenext step. HRMS m/z calcd for C₆H₈N₂O₂ (M)⁺ 140.0586, found 140.0589.

[0783] Step 2:2-[2-(5-Pyrimidinyloxy)ethoxy]-3-(1-piperazinyl)quinoxaline.

[0784] The title compound was prepared according to the proceduredescribed in Example 162, Step 2, starting from2-chloro-3-(1-piperazinyl)quinoxaline (0.66 g, 2.65 mmol; from Example162, Step 1) and 2-(5-pyrimidinyloxy)ethanol (0.45 g, 3.20 mmol). Yield0.55 g (59%); mp 115-117° C.; HRMS m/z calcd for C₁₈H₂₀N₆O₂ (M)⁺352.1648, found 352.1654. Anal. (C₁₈H₂₀N₆O₂) C, H, N.

Example 167

[0785]2-(3,4-Dihydro-2H-1,4-benzoxazin-2-ylmethoxy)-3-(1-piperazinyl)quinoxaline,0.5 Fumarate.

[0786] The title product was prepared according to the proceduredescribed in Example 162, Step 2, starting from2-chloro-3-(1-piperazinyl)quinoxaline (described in Example 162. Step 1)and 3,4-dihydro-2H-1,4-benzoxazin-2-ylmethanol.

Example 168

[0787]2-(3,4-Dihydro-2H-chromen-2-ylmethoxy)-3-(1-piperazinyl)quinoxaline.

[0788] The title product was prepared according to the proceduredescribed in Example 162, Step 2, starting from2-chloro-3-(1-piperazinyl)quinoxaline (described in Example 162. Step 1)and 3.4-dilydro-2H-clromen-2-ylmethanol.* The product was obtained as ayellow amorphous substance: yield 23%; mp 202-204° C.; HRMS m/z calcdfor C₁₃H₁₆N₄O₂ (M)⁺ 376.1899, found 376.1899. Anal. (C₂₂H₂₄N₄O₂.HCl) H;C: calcd, 61.32; found, 60.7; N: calcd, 13.00; found 13.5.

Example 169

[0789] 2,3-Dihydro-1,4-benzodioxin-2-ylmethyl3-(4-methyl-1-piperazinyl)-2-pyrazinyl ether, Dihydrochloride.

[0790] Step 1: 1-(3-Chloro-2-pyrazinyl)-4-methylpiperazine.

[0791] A mixture of 2,3-dichloropyrazine (10.1 g, 68 mmol) andN-methylpiperazine (10.15 g, 100 mmol) in acetonitrile (250 mL) wasstirred at room temperature for 60 h. The solvent was removed underreduced pressure and the residue was taken up in CHCl₃/brine. The dried(MgSO₄) organic layer was concentrated and the remaining oil waspurified by chromatography on silica gel using CHCl₃/MeOH (95:5) aseluent to give 10.7 g (75%) of the title compound as an oil thatcrystallized upon standing: mp 34-36° C. Anal. (C₉H₁₃ClN₄) C, H, N.

[0792] Step 2: 2,3-Dihydro-1,4-benzodioxin-2-ylmethyl3-(4-methyl-1-piperazinyl)-2-pyrazinyl ether, Dihydrochloride.

[0793] The title compound was prepared according to the proceduredescribed in Example 90, Step 2, starting from1-(3-chloro-2-pyrazinyl)-4-methylpiperazine (described in Example 169,Step 1) and 2-hydroxymethyl-2,3-dihydro-1,4-benzodioxine. Yield 87%; mp160-167° C. Anal. (C₁₈H₂₂N₄O₃.2HCl) H, N; C: calcd, 52.06; found, 52.6.

Example 170

[0794] 2-(Phenoxy)ethyl-3-(4-methyl-1-piperazinyl)-2-pyrazinyl ether,Hydrochloride.

[0795] The title compound was prepared according to the proceduredescribed in Example 90, Step 2, startingfrom]-(3-chloro-2-pyrazinyl)-4-methylpiperazine (described in Example169, Step 1) and 2-phenoxyethanol. Yield 79%; mp 172-174° C. Anal.(C₁₇H₂₂N₄O₂HCl) C, H, N.

Example 171

[0796] 2-(2-Phenoxy)ethyl 3-(2-methyl-1-piperazinyl)-2-pyrazinyl ether,Maleate.

[0797] Step 1: 3-Chloro-2-(4-benzyl-2-methyl-1-piperazinyl)pyrazine.

[0798] A mixture of 2,3-dichloropyrazine (0.332 g, 2.23 mmol),1-benzyl-3-methylpiperazine* (0.423 g, 2.23 mmol), and K₂CO₃ (0.339 g,2.45 mmol) in acetonitrile (2.5 mL) was stirred at 115° C. for 17 h in asealed tube. The reaction mixture was diluted with ether, filtered, andconcentrated. The brownish oily residue was purified by chromatographyon silica gel using n-hexane/EtOAc (7:3) as eluent to give 0.19 g (28%)of the title product as a viscous oil that was sufficiently pure for thenext step.

[0799] Step 2: 2-(2-Phenoxy)ethyl3-(4-benzyl-2-methyl-1-piperazinyl)-2-pyrazinyl ether.

[0800] KO-t-Bu (0.087 g, 0.77 mmol) was added in one portion to astirred solution of 2-phenoxyethanol (0.164 g, 1.19 mmol) in dioxane (5mL) at room temperature. After being stirred for 5 min at 90° C., asolution of the product obtained in Step 1 above (0.18 g, 0.59 mmol) indioxane (3 mL) was added. The mixture was stirred at room temperaturefor 10 min and at 85° C. for 2 h. The reaction mixture was diluted withether, filtered, and concentrated. The remaining beige oil was purifiedby chromatography on silica gel using n-hexane/EtOAc (7:3) as eluent togive 0.22 g (93%) of the title product as an oil. HRMS m/z calcd forC₂₄H₂₈N₄O₂ (M)⁺ 404.2212, found 404.2232.

[0801] Step 3: 2-(2-Phenoxy)ethyl 3-(2-methyl-1-piperazinyl)-2-pyrazinylether, Maleate.

[0802] Ammonium formate (0.18 g, 2.85 mmol) was added to a solution ofthe product from Step 2 above (0.22 g, 0.54 mmol) in ethanol (5 mL). Themixture was purged with nitrogen and 5% Pd/C (0.15 g) was added. Theflask was sealed and the mixture as stirred at 90° C. for 2.5 h. Thereaction mixture was filtered through Celite and concentrated. Theresidue was purified by chromatography on silica gel using CHCl₃/MeOH(110:1) to give 0.12 g (72%) of the free base of the title compound asan oil. The free base was converted to the maleate and recrystallizedfrom MeOH/ether; mp 102-103° C.; HRMS m/z calcd for C₁₇H₂₂N₄O₂ (M)⁺314.1743, found 314.1754. Anal. (C₁₇H₂₂N₄O₂.C₄H₄O₄) C, H, N.

Example 172

[0803] (2R)-Methyl-1-[3-(2-phenoxyethoxy)-2-pyrazinyl]piperazine,Hydrochloride.

[0804] Step 1: 4-tert-Butoxycarbonyl-(2R)-methylpiperazine.

[0805] Glacial acetic acid (6.3 g, 105 mmol), followed bydi-tert-butyldicarbonate (23.11 g, 106 mmol), were added to a stirredsolution of (2R)-methylpiperazine (10.3 g, 103 mmol) in MeOH (200 mL) at0° C., and the resulting mixture was stirred for 1 h. The reactionmixture was allowed to warm to room temperature and stirred for further15 h. An excess of triethylamine (20 mL, 140 mmol) was added and thereaction mixture was concentrated under reduced pressure. The residuewas suspended in CHCl₃ and filtered through a fritted glass filter. Thefiltrate was concentrated, and the residue was purified bychromatography on silica gel using CHCl₃/MeOH (85:15) as eluent to give21 g (65%) of the title product as an oil that crystallized uponstanding. The product was used in the next step without furthercharacterization.

[0806] Step 2:3-Chloro-2-[4-tert-butoxycarbonyl-(2R)-methyl-1-piperazinyl]pyrazine.

[0807] A mixture of 2,3-dichloropyrazine (22.0 g, 148 mmol),4-tert-butoxycarbonyl-(2R)-methylpiperazine (21 g, 105 mmol) and K₂CO₃(30.4 g, 220 mmol) in DMF was heated at 95° C. for 15 h. The blackreaction mixture was filtered through a bed of silica gel, and thefiltrate was concentrated. The residue was purified by chromatography onsilica gel using petroleum ether/EtOAc (9:1) as eluent to afford 3.2 g(10% over two steps) of the title compund as a colourless oil. HRMS m/zcalcd for C₁₄H₂₁ClN₄O₂ (M)⁺ 312.1353, found 312.1358.

[0808] Step 3:(2R)-Methyl-1-[3-(2-phenoxyethoxy)-2-pyrazinyl]piperazine,Hydrochloride.

[0809] KO-t-Bu (0.52 g, 4.66 mmol) was added to a solution of2-phenoxyethanol (0.42 g, 3.0 mmol) in dioxane (15 mL) and the mixturewas stirred at room temperature for 15 minutes.4-tert-Butoxycarbonyl-(2R)-methylpiperazine (0.73 g, 2.33 mmol; fromStep 1 above) was added to the suspension and the reaction was stirredat 85° C. for 15 h. The reaction mixture was filtered through Celite andthe filtrate was concentrated under reduced pressure. The crude productwas purified by chromatography on silica gel using CHCl₃/MeOH/NH₄OH(97:3:0.2) as eluent. The resulting oil was dissolved in CH₂Cl₂₁TFA(1:1) and the mixture was stirred at room temperature for 15 h. Themixture was concentrated under reduced pressure and the remaining oilwas partitioned between 1 M NaOH/CHCl₃. The organic phase was dried(MgSO₄) and the solvent evaporated. The resulting oil was purified bychromatography on silica gel using CHCl₃/MeOH/NH₄OH (95:5:0.2) as eluentto provide the free base of the title compound. The free base wasprecipitated as its hydrochloride salt with HCl/ether to give 0.36 g(44%) of the title compound as white crystals: mp 164-166° C.; HRMS m/zcalcd for C₁₇H₂₂N₄O₂ (M)⁺ 314.173 1, found 314.1743. Anal. (C₁₇H₂₂N₄O₂HCl) C, H, N.

[0810] Examples 173-177 were prepared according to the procedure ofExample 172, step 3.

Example 173

[0811](2R)-Methyl-1-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinylpiperazine,Hydrochloride.

[0812] The title compound was prepared starting from2-(3-pyridyloxy)ethanol (from Example 150, Step 1) and3-chloro-2-[4-tert-butoxycarbonyl-(2R)-methyl-1-piperazinyl]pyrazine(from Example 172, Step 2). The pure free base was precipitated as itshydrochloride salt with HCl/ether to give the title compound as whitecrystals: yield 31%; mp 180-183° C.; HRMS m/z calcd for C₁₆H₂₁N₅O₂ (M)⁺315.1695, found 315.1689. Anal. (C₁₆H₂₁N₅O₂.1.33HCl) C, H, N.

Example 174

[0813] (2S)-Methyl-1-{3-[2-(3-pyridinoxy)ethoxy]-2-pyrazinyl}piperazine,Hydrochloride.

[0814] The title compound was prepared starting from2-(3-pyridyloxy)ethanol (from Example 150, Step 1) and3-chloro-2-[4-tert-butoxycarbonyl-(2S)-methyl-1-piperazinyl]pyrazine(prepared according to the procedure of Example 172, Step 2, with theexception that 2S)-methylpiperazine was substituted for(9R)-methylpiperazine). MS m/z 316 (M+H)⁺.

[0815] Yield 58%, mp 170-172° C. Anal. (C₁₆H₂₁N₅O₂.1.45 HCl) C, H, N.

Example 175

[0816] (2S)-Methyl-1-[3-(2-phenoxyethoxy)-2-pyrazinyl]piperazine,Hydrochloride.

[0817] The title compound was prepared starting from 2-phenoxy-1-ethanoland 3-chloro-2-[4-tert-butoxycarbonyl-(2S)-methyl-1-piperazinyl]pyrazine(prepared according to the procedure of Example 172, Step 2, with theexception that (2S)-methylpiperazine was substituted for(2R)-methylpiperazine). MS m/z 315 (M+H)⁺. Yield 68%; mp 162-163° C.Anal. (C₁₇H₂₂N₄O₂.HCl) C, H, N.

Example 176

[0818](2R)-2-Methyl-1-(3-[2-[(6-methyl-3-pyridinyl)oxy]ethoxy)-2-pyrazinyl)piperazine,Fumarate.

[0819] The title product was prepared from2-(6-methyl-3-pyridyloxy)ethanol (from Example 153, Step 1) and3-chloro-2-[4-tert-butoxycarbonyl-(2R)-methyl-1-piperazinyl]pyrazine(from Example 172, Step 2). The crude product was purified by columnchromatography on silica using CHCl₃/MeOH/NH₄OH (95:5:0.2) as eluent.After evaporation of the solvent from the combined pure fractions, theresulting free base was precipitated as its fumaric acid salt.Recrystallization from MeOH/ether gave 46% of the title product as anamorphous solid: mp 115° C. (dec). Anal. (C₁₇H₂₃N₅O₂.C₄H₄O₄) C, H, N.

Example 177

[0820](2R)-Methyl-1-{3-[2-(2-amino-8-quinolinyloxy)ethoxy]-2-pyrazinyl}piperazine,Fumarate.

[0821] Step 1: 2-(2-Amino-8-quinolinyloxy)-ethanol.

[0822] A mixture of 2-amino-8-quinolinol (3.20 g, 20.0 mmol), ethylenecarbonate (1.76 g, 20.0 mmol) and KO-t-Bu (2.24 g, 20.0 mmol) in DMF (20mL) was stirred at 90° C. for 15 h. The mixture was poured into brine,extracted with EtOAc, dried (MgSO₄), and concentrated under reducedpressure. The residue was purified by chromatography on silica gel usingtoluene/EtOAc/MeOH (50:50:2) as eluent to give 1.13 g (28%) of the titleproduct as a solid. HRMS m/z calcd for C₁₁H₁₂NO₂ (M)⁺ 204.0899, found204.0906.

[0823] Step 2:(2R)-Methyl-1-{3-[2-(2-amino-8-quinolinyloxy)ethoxy]-2-pyrazinyl}piperazine,Fumarate.

[0824] The title compound was prepared starting from2-(2-amino-8-quinolinyloxy)ethanol and3-chloro-2-[4-tert-butoxycarbonyl-(2R)-methyl-1-piperazinyl]pyrazine(from Example 172, Step 2). The pure free base was precipitated as itsfumaric acid salt to give the title compound as yellow, slightlyhygroscopic, crystals: yield 5%; mp 160-163° C. (dec). HRMS m/z calcdfor C₂₀H₂₄N₆O₂ (M)⁺ 380.1961, found 380.1958.

Example 178

[0825] 2-Ethyl-1-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine,Fumarate.

[0826] Step 1: 1-Benzyl-3-ethylpiperazine.

[0827] Benzyl bromide (38.7 g, 0.22 mol) was added in portions to an icecold (0° C.) solution of 2-ethylpiperazine (25 g, 0.22 mol) in DMF (150mL) with such a rate that the temperature did not exceed 20° C. Themixture was stirred for 1 h, the solvent was evaporated and the residuewas partitioned between CHCl₃/0.5 M HCl. The aqueous phase was madealkaline (11M NaOH) and extracted three times with CHCl₃. The combinedorganic phases were dried (MgSO₄) and concentrated. The resulting oilwas purified by column chromatography on silica using CHCl₃, followed byCHCl₃/MeOH/NH₄OH (95:5:0.3) as eluents to give 31.6 g (70%) of the titlecompound as a yellowish oil. Anal. (C₁₃H₂₀N₂) H, N; C: calc, 76.42 found75.85; H, N.

[0828] Step 2: 4-Benzyl-1-(3-chloro-2-pyrazinyl)-2-ethylpiperazine.

[0829] A mixture of 2,3-dichloropyrazine (3.9 g, 27 mmol),1-benzyl-3-ethylpiperazine (4.6 g, 22.5 mmol; from Step 1) and K₂CO₃(6.2 g, 45 mmol) in DMF (10 mL) was stirred at 100° C. for 4 days. Thesolvent from the filtered reaction mixture was evaporated off and theresidue was purified by column chromatography on silica usingheptane/EtOAc (90:10) as eluent to yield 5.0 g (71%) of the titlecompound as a light yellow oil. HRMS m/z calcd for C₁₇H₂₁ClN₄ (M)⁺316.1455, found 316.1448.

[0830] Step 3:1-(3-Chloro-2-pyrazinyl)-2-ethylpiperazine, Hydrochloride.

[0831] 1-Chloroethyl chloroformate (2.11 g, 15.2 mmol) was added with asyringe during 1 h to an ice cold (˜0° C.) solution of4-benzyl-1-(3-chloro-2-pyrazinyl)-2-ethylpiperazine (3.22 g, 10.1 mmol,from Step 2) in dry CH₂Cl₂ (30 mL). The reaction-was allowed to slowlyreach room temperature and stirred for 48 h. The solvent was evaporatedfrom the reaction mixture and MeOH was added to the resulting oil. Themixture was heated to reflux for 2 h, the solvent was evaporated and theresulting oil was partitioned between CHCl₃/H₂O. The aqueous phase wasmade alkaline and extracted with CHCl₃ (×3). The combined organic phaseswere dried (MgSO₄), and the solvent was evaporated. The resulting oilwas purified by column chromatography on silica using CHCl₃/MeOH/NH₄OH(95:5:0.2) as eluent to give a quantitative yield (2.35 g) of the freebase of the title compound as a slightly yellow oil. An analyticalsample was prepared as its hydrochloric acid salt (from HCl/ether): mp195-197° C. Anal. (C₁₀H₁₅ClN₄.HCl) C, H, N.

[0832] Step 4,2-Ethyl-1-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine,Fumarate.

[0833] The title compound was prepared starting from2-(3-pyridyloxy)ethanol (from Example 150, Step 1) and the productobtained in Step 3 according to the procedure described in Example 162,Step 2. The crude product was purified by column chromatography onsilica using CHCl₃/MeOH/NH₄OH (90:10:0.3) as eluent. After evaporationof the solvent from the combined pure combined fractions, the resultingfree base was converted to its fumarate salt and crystallized from MeOHto afford 0.21 g (8%) of the title compound as light yellow crystals: mp125-127° C.; HRMS m/z calcd for C₁₇H₂₃N₅O₂ (M)⁺ 329.1852, found329.1845. Anal. (C₁₇H₂₃N₅O₂.C₄H₄O₄) C, H, N.

Example 179

[0834]cis-2.6-Dimethyl]-1-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine,Fumarate.

[0835] Step: 1-Benzyl-cis-3,5-dimethylpiperazine.*

[0836] To an ice cold (˜0° C.) suspension of cis-2,6-dimethylpiperazine(4.0 g, 35 mmol) in DMF (100 mL).was benzyl bromide (6.0 g, 35.0mmol)added in portions under a period of 45 mill and the reactionmixture was stirred at room temperature for 48 h. The solvent wasevaporated from the suspension and the residue was dissolved in aqueousHCl and washed twice with CHCl₃. The aqueous phase was made alkaline andextracted twice with CHCl₃. The combined organic phases were washed withH₂O and brine, dried (MgSO₄), and concentrated to give 4.9 g (68%) ofthe title product as a colorless oil.

[0837] Step 2:4-Benzyl-1-(3-chloro-2-pyrazinyl)-cis-2,6-dimethylpiperazine.

[0838] A mixture of 2,3-dichloropyrazine (4.9 g, 32.9 mmol),1-benzyl-cis-3,5-dimethylpiperazine (5.9 g, 29.0 mmol), tributylamine(5.9 g, 32 mmol) and diphenyl ether (70 mL) was heated in a sealed tubeat 220° C. for 3 days. The reaction mixture was cooled to ambienttemperature and EtOAc (200 mL) and toluene (100 mL) were added. Theorganic phase was extracted with 5 M aqueous HCl (×3) and the combinedaqueous phases were extracted with CHCl₃ (×3). The combined organiclayers, which contained the product, were washed with aqueous NaOH (5M), dried (MgSO₄), and the solvent was evaporated. The crude product(0.96 g), about 80% pure based on GC, was used in the next step withoutfurther purification.

[0839] Step 3, 1-(3-Chloro-2-pyrazinyl)-cis-2,6-dimethylpiperazine,Hydrochloride.

[0840] The title compound was prepared by treating the product obtainedin Step 2 with 1-chloroethyl chloroformate according to the proceduredescribed in Example 178, Step 3. The crude product was purified bycolumn chromatography on silica using CHCl₃/MeOH/NH₄OH (95:5:0.2,followed by 90:10:0.5) as eluent to give 0.50 g (8% over two steps) ofthe free base of the title compound as a colorless oil. An analyticalsample vas precipitated as its HCl salt with HCl/ether: mp 199-200° C.Anal. (C₁₀H₁₅ClN₄.HCl) C, H, N.

[0841] Step 4:cis-2,6-Dimethyl-1-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine,Fumarate.

[0842] The title compound was prepared starting from2-(3-pyridyloxy)ethanol (from Example 150. Step 1) and the productobtained in Step 3 according to the procedure of Example 162. Step 2.The crude product was purified by column chromatography on silica usingCHCl₃/MeOH/NH₄OH (95:5:0.2) as eluent. After evaporation of the solventfrom the combined pure fractions, the resulting oil was crystallized asits fumaric acid salt from MeOH/ether to afford 0.29 g (36%) of thetitle compound as white crystals: mp 157° C. (dec). Anal. (C₁₇H₂₃N₅O₂*C₄H₄O₄) C, H, N.

Example 180

[0843]N-[8-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-2-quinolinyl]acetamide.

[0844] Step 1: tert-Butyl4-(3-{2-[(2-amino-8-quinolinyl)oxy]ethoxy}-2-pyrazinyl)-1-piperazinecarboxylate.

[0845] The product of Example 177, Step 1 (503 mg, 2.46 mmol) and2-chloro-3-(4-tert-butoxycarbonyl-1-piperazinyl)pyrazine (659 mg, 2.21mmol, from Example 52, Step 1) were dissolved in dry dioxane (20 mL).K-t-Bu (305 mg, 2.72 mmol) was added and the reaction mixture washeated. The reaction mixture was heated at 80° C. under inert atmospherefor 3.5 h (monitoring by MS). The reaction mixture was concentrated invacuo and the residue was dissolved in EtOAc. The organic phase waswashed with H₂O and the aqueous phase was back-extracted with CH₂Cl₂.The combined organic phases were washed with brine and dried (MgSO₄).Evaporation of the solvents gave a yellow oil (1.37 g), that waspurified by column chromatography using EtOAc/Et₃N (95:5) as eluent togive the title compound as a yellow solid: yield 898 mg (87%); MS m/z467 (M+H)⁺. Anal. (C₂₄H₃₀N₆O₄.0.9H₂O)C, H, N.

[0846] Step 2: tert-Butyl4-[3-(2-[{2-(acetylamino)-8-quinolinyl]oxy}ethoxy)-2-pyrazinyl]-1-piperazinecarboxylate.

[0847] The product obtained in Step 1 (502 mg, 1.08 mmol) was dissolvedin pyridine. Ac₂O (0.42 mL, 4.45 mmol),as added, and the reactionmixture was stirred under inert atmosphere at room temperature for 5 h.Concentration in vacuo afforded a yellow oil, which as purified bycolumn chromatography using EtOAc/Et₃N (95:5) as eluent to give thetitle product as a yellow solid: yield 531 mg (97%); MS m/z 509 (M+H)⁺.Anal. (C₂₆H₃₂N₆O₅ 0.4H₂O)C, H, N.

[0848] Step 3:N-[8-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-2-quinolinyl]acetamide.

[0849] TFA (1.5 mL) was added to a solution of the product from Step 2(112 mg, 0.22 mmol) in CHCl₂ (1.5 mL) at 0° C. and the mixture wasstirred under inert atmosphere for 1 h. The reaction mixture was dilutedwith CH₂Cl₂ and washed with 2 M aqueous NaOH (x 4) and brine. Theorganic layer was dried (MgSO₄) and concentrated. The crude solidproduct (83 mg) was purified by column chromatography on silica usingCHCl₃/MeOH (9:1)+1% NH₃ as eluent to give the title compund as an oilthat solidified after repeated additions of pentane: yield 67 mg (75%);MS m/z 409 (M+H)⁺. Anal. (C₂₁H₂₄N₆O₃.0.6H₂O.0.1C₅H₁₂) C, H, N.

Example 181

[0850]N-Methyl-8-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-2-quinolinamine.

[0851] Step 1: 2-(Methylamino)-8-quinolinol.

[0852] To a solution of 2-chloro-8-hydroxyquinoline* (2.0 g, 11.1 mmol)in EtOH (40 mL) was added H₂NMe (40% aqueous solution, 40 mL, 464 mmol).The mixture was heated in a sealed Pyrex tube at 100° C. for 24 h. Thesolvent was evaporated and the resulting crude product was purifiedb)_(y) column chromatography [gradient: CH₂Cl₂/MeOH (99:1) to 1% NH₄OHin CH₂Cl₂/MeOH (80:20)] to give the title compound as a black-greensolid. Yield 1.31 g (67%) MS m/z 174 (M)⁺. Anal. (C₁₀H₁₀N₂O) C, H, N.

[0853] Step 2: 2-{[2-(Methylamino)-8-quinolinyl]oxy}-1-ethanol.

[0854] The title compound was prepared according to the procedure ofExample 91, Step 1, starting from the product obtained in Step 1 above.The crude product as purified by column chromatography on silica gelusing EtOAc/MeOH (95:5) containing Et₃N (2%). Solid; yield 1.21 g (88%);MS m/z 218 (M)⁺. Anal. (C₁₂H₁₄N₂O₂.0.6H₂O)C, H, N.

[0855] Step 3:N-Methyl-8-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)-2-quinolinamine.

[0856] The title compound was prepared according to the procedure ofExample 90, Step 2, starting from the product obtained in Step 2 aboveand 2-chloro-3-(1-piperazinyl)piperazine (from Example 90, Step 1). Thecrude product was purified by column chromatography (gradient: 1% NH₄OHin EtOAc/MeOH (90:10) to 1% NH₄OH in EtOAc/MeOH (80:20) in firstpurification step and gradient 0.5% NH₄OH in CHCl₃/MeOH (95:5) to 1%NH₄OH in CHCl₃/MeOH (90:10) in second purification). Yield 31%; mp54.0-56.5° C.; MS m/z 381 (M+H)⁺. Anal. (C₂₀H₂₄N₆O₂.0.5H₂O) C, H, N.

Example 182

[0857]2-[2-(1,3-Benzodioxol-4-yloxy)ethoxy]-3-(2-methyl-1-piperazinyl)quinoxaline,Hydrochloride.

[0858] Step 1: Step 1: 4-tert-Butoxycarbonyl-2-methylpiperazine.*

[0859] The title compound was prepared according to the proceduredescribed in Example 172, Step 1, except that racemic 2-methylpiperazinewas used instead of (2R)-methylpiperazine. Yield 82% of the free base.An analytical sample was prepared by conversion to the hydrochloridesalt: mp 162° C. (dec). Anal. (C₁₀H₂₀N₂O₂.HCl) C, H, N.

[0860] Step 2: tert-Butyl4-(3-chloro-2-quinoxalinyl)-3-methyl-1-piperazinecarboxylate.

[0861] A mixture of the title product from Step 1 above (12.3 g, 61.4mmol), 2,3-dichloroquinoxaline (14.4 g, 72.2 mmol), and K₂CO₃ (13.8 g,100 mmol) in DMF (100 mL) was stirred at 85° C. for 15 h. The mixturewas filtered and the resulting filtrate was concentrated under reducedpressure. The residue was purified by chromatography on silica eel usingpetroleum ether/EtOAc (94:6) as eluent to give 5.8 g (36/0%) of areddish oil that crystallized on standing: mp 93-97° C. Anal.(C₁₈H₂₃ClN₄O₂) C, H, N.

[0862] Step 3: 2-(1,3-Benzodioxol-4-yloxy)ethanol.

[0863] A mixture of 1,3-benzodioxol-4-ol* (0.74 g, 5.36 mmol), ethylenecarbonate (0.47 g, 5.3 mmol) and K₂CO₃ (0.67 g, 4.8 mmol) in DMF (30 mL)was heated at 150° C. After the evolution of carbon dioxide had ceased(1 h), the reaction mixture was filtered and concentrated. The crudeproduct was purified by chromatography on silica gel using petroleumether/EtOAc (70:30) as eluent to give 0.64 g (65%) of the title productas an oil which spontaneously crystallized to a white solid: mp 56-57°C. Anal. (C₉H₁₀O₄) C, H.

[0864] Step 4:2-[2-(1,3-Benzodioxol-4-yloxy)ethoxy]-3-(2-methyl-1-piperazinyl)quinoxaline,Hydrochloride.

[0865] KO-t-Bu (0.41 g, 3.7 mmol) was added to a solution of2-(1,3-benzodioxol-4-yloxy)ethanol (0.33 g, 1.8 mmol; from Step 3 above)in dioxane (15 mL). After 15 min of stirring at room temperature, thetitle compound from Step 2 above (0.73 g, 2.0 mmol) was added and themixture was stirred at 95° C. for 1.5 h. The reaction mixture wasfiltered through a pad of Celite, concentrated in vacuo, and the residuewas purified by chromatography on silica gel using petroleum ether/EtOAc(9:1) as eluent. The resulting oil was dissolved in CH₂Cl₂/TFA (1: 1, 20mL) and stirred at room temperature for 15 h. The mixture wasconcentrated and the resulting oil was co-evaporated twice with 2 M HCl.The residue was recrystallized from water to give 0.22 g (26%) of thetitle compound as white crystals: mp 133-138° C.; HRMS m/z calcd forC₁₇H₂₂N₄O₂ (M)⁺ 408.1798, found 408.1782. Anal. (C₂₂H₂₄N₄O₄.HCl.H₂O) C,H, N.

Example 183

[0866] 5,6-Dimethyl-2-(2-phenoxyethoxy)-3-(1-piperazinyl)pyrazine,Dihydrochloride.

[0867] Step 1, 2-Chloro-5,6-dimethyl-3-(1-piperazinyl)pyrazine.

[0868] The title compound was prepared according to the proceduredescribed in Example 90. Step 1, starting from2,3-dichloro-5,6-dimethylpyrazine* (0.60 g. 3.39 mmol) and piperazine(0.88 g. 10.2 mmol). Yield 0.51 g (66%). MS m/z 226 (M).

[0869] Step 2:5,6-Dimethyl-2-(2-phenoxyethoxy)-3-(1-piperazinyl)pyrazine,Dihydrochloride.

[0870] The product from Step 1 above (506 mg, 2.20 mmol) and2-phenoxyethanol (370 mg, 2.70 mmol) was dissolved in dioxane (10 mL).KO-t-Bu (626 mg, 5.60 mmol) was added and the resulting mixture wasstirred at 95° C. for 4 h. The solvent was evaporated and the residuewas purified by chromatography on silica gel to give the free base as ayellow oil. The free base was converted to the dihydrochloride saltwhich was obtained as a monohydrate: yield 0.46 g (50%); mp 138-140° C.Anal. (C₁₈H₂₄N₄O₂.2HCl.H₂O) C, H, N.

Example 184

[0871] 1-[2-(2-Phenoxyethoxy)phenyl]piperazine, Hydrochloride.

[0872] Step 1: tert-Butyl 4-(2-hydroxyphenyl)-1-piperazinecarboxylate.

[0873] Triethylamine (8.23 mL, 59.5 mmol) was added to a stirredsolution of 2-(1-piperazinyl)phenol dihydrobromide (9.87 g, 29.0 mmol)in a mixture of water and dioxane (1: 1, 60 mL). The reaction mixturewas cooled on an ice-bath (0° C.) and di-tert-butyldicarbonate (6.33 g,29.0 mmol) was added in one portion. The resulting mixture was allowedto warm to room temperature and stirred for 15 h. The mixture wasconcentrated to a small volume. Water (20 mL) was added and the whitecrystals formed were filtered off and dried (1 mm Hg, 70° C.) to give aquantitative yield (7.24 g) of the title compound: mp 115-117° C. Anal.(C₁₅H₂₂N₂O₃) C, H, N.

[0874] Step 2: 1-[2-(2-Phenoxyethoxy)phenyl]piperazine, Hydrochloride.

[0875] The product from Step 1 above (0.55 g, 2.0 mmol) was added to astirred solution of NaO-t-Bu (0.55 g, 2.0 mmol) in DME (5 mL). After 5min, β-bromophenetole (0.56 g. 2.8 mmol) was added, and the reaction wasstirred at 55° C. for 15 h. 2 M HCl was added, and the reaction mixturewas stirred for another 3 h. The reaction mixture was concentrated invacuo and the residue was partitioned between 2 M NaOH/CHCl₃. Theaqueous phase was extracted with CHCl₃ (×3). The combined organic layerswere dried (MgSO₄) concentrated, and the residue was purified bychromatography on silica gel using CHCl₃/MeOH/NH₄OH (90:10:0.4) aseluent to give the free base of the title compound. The free base wastreated with HCl/ether, and the resulting hydrochloride salt was dried(80° C., 1 mmHg) to afford 0.254 g (35%) of the title compound as alight brown semi-solid material that solidified upon standing. Anal.(C₁₈H₂₂N₂O₂ HCl H₂O)H, N; C: calc, 61.27; found, 61.9.

Example 185

[0876] 1-[3-(2-Phenoxyethoxy)-2-pyridinyl]piperazine, Dihydrochloride.

[0877] Step 1: 2-Chloro-3-(2-phenoxyethoxy)pyridine.

[0878] A mixture of 2-chloro-3-hydroxypyridine (3.0 g, 23.1 mmol),β-bromophenetole (4.66 g, 23.2 mmol), and K₂CO₃ (8.0 g, 57.9 mmol) inDMF (50 mL) was heated at 100° C. for 1.5 h. The solvent was removedunder reduced pressure and the residue was partitioned between EtOAc andH₂O. The organic phase was dried (MgSO₄), filtered, and the solventevaporated. The solid residue was triturated with a small amount ofether and dried (65° C., 1 mmHg) to afford 4.23 g (74%) of the titleproduct as white crystals: mp 77-780C. Anal. (C₁₃H₁₂ClNO₂) C, H, N.

[0879] Step 2: 1-[3-(2-Phenoxyethoxy)-2-pyridinyl]piperazine,Dihydrochloride.

[0880] A mixture of the product from Step 1 above (0.84 g, 3.1 mmol) andpiperazine hexahydrate (5.3 g, 27.3 mmol) was heated in a sealed tube at165° C. for 1 h. After cooling, the mixture was diluted with water (100mL) and extracted twice with EtOAc. The combined and dried (MgSO₄)organic phases were concentrated in vacuo and the residue was purifiedby chromatography on silica gel using CHCl₃/MeOH/NH₄OH (90:10:0.4) aseluent to give the free base of the title compound. The free base wastreated with HCl/ether, and the resulting dihydrochloride salt was dried(80° C., 1 mmHg) to afford 0.598 g (52%) of the title compound as alight yellow solid: mp 91-120° C. Anal. (C₁₇H₂₁N₃O₂ 2HCl) C, H, N.

Example 186

[0881] 2-(2,3-Dihydrobenzofuran-7-yloxy)ethyl3-(1-piperazinyl)-2-pyrazinyl ether, Maleate.

[0882] The title compound obtained in Example 140, Step 2, (390 mg, 0.85mmol) was dissolved in MeOH (50 mL) and hydrogenated over 10% Pd/C (50mg) at atmospheric pressure for 7 h. The reaction mixture was filteredthrough Celite and concentrated. The residue was purified bychromatography on silica gel using EtOAc/MeOH/Et₃N (9:1:0.25) as eluentto give 57 mg (20%) of the free base of the title compound. The freebase was converted to the maleate and recrystallized from MeOH/ether: mp149-154° C.; MS m/z 343 (M+H)⁺. Anal. (C₁₈H₂₂N₄O₃.1.1C₄H₄O₄.0.6H₂O) C,H, N.

Example 187

[0883] 5-Chloro-2-(1-piperazinyl)-3-[2-(3-pyridinyloxy)ethoxyl pyrazine,Fumarate.

[0884] Step 1: 3,5-Dichloro-2-(1-piperazinyl)pyrazine.

[0885] To a suspension of 2-chloro-3-(1-piperazinyl)pyrazine (11.7 g,58.7 mmol; from Example 90, Step 1) in CHCl₃ (50 mL) wasN-chlorosuccinimid (14.4 g, 108 mmol) added and the mixture was heatedat reflux for 30 minutes. The reaction mixture was cooled to ambienttemperature and extracted twice with water. The combined aqueous phaseswere made alkaline (11 M NaOH), saturated with NaCl, cooled, andextracted with EtOAc (×3). Concentration of the combined, dried (MgSO₄),organic phases afforded 6.12 g (45%) of the title compound as a brownoil which crystallized upon standing: mp 89-97° C. Anal.(C₈H₁₀Cl₂N₄.1/3H₂O) C, H, N.

[0886] Step 2:5-Chloro-2-(1-piperazinyl)-3-[2-(3-pyridinyloxy)ethoxy]pyrazine,Fumarate

[0887] The title compound was prepared starting from2-(3-pyridyloxy)ethanol (from Example 150. Step 1) and the product fromStep 1 according to the procedure described in Example 162, Step 2. Thecrude product as purified by column chromatography on silica usingCHCl₃/MeOH/NH₄OH (95:5:0.2, followed by 90:10:0.3) as eluent. Afterevaporation of the solvent from the combined pure fractions, theresulting oil was crystallized as its fumaric acid salt from MeOH/etherto afford 3.06 g (39%) of the title compound as light yellow crystals:mp 162° C. (dec). Anal. (C₁₅H₁₈ClN₅O₂.C₄H₄O₄) C, H, N.

Example 188

[0888] 5-Bromo-2-(1-piperazinyl)-3-[2-(3-pyridinyloxy)ethoxy]pyrazine,Acetate.

[0889] Step 1: 5-Bromo-3-chloro-2-(1-piperazinyl)pyrazine.

[0890] To a mixture of 2-chloro-3-(1-piperazinyl)pyrazine (5.94 g, 30mmol, from Example 90. Step 1) and Na₂CO₃ (6.0 g, 57 mmol) in AcOH (25mL) was added a solution of Br₂ (6.00 g, 38.0 mmol) in AcOH (25 mL)dropwise at room temperature. The reaction mixture was stirredovernight. Water (50 mL) was added and the solution was stirred for 30min and then concentrated to a small volume. Water (20 mL) was added andthe solution was basified to pH 9 by adding solid Na₂CO₃. The mixturewas extracted with CH₂Cl₂ containing 10% MeOH. The combined extract wasevaporated to dryness and the residue was recrystallized from MeOH togive 7.43 g (89%) of the title compound: mp 114-115° C. HRMS m/z calcdfor C₈H₁₀BrClN₄ (M)⁺ 275.9777, found 275.9765.

[0891] Step 2: 5-Bromo-2-(1-piperazinyl)-3-[2-(3-pyridinyloxy)ethoxy]pyrazine, Acetate.

[0892] To a solution of the product obtained in Step 1 above (3.73 g,13.5 mmol) and 2-(3-pyridyloxy)ethanol (2.06 g, 14.8 mmol, from Example150, Step 1) in DMSO (10 mL) was added NaH (50% in mineral oil; 0.93 g,20 mmol) at room temperature. The mixture was stirred at roomtemperature overnight. EtOAc (100 mL) was added and the mixture waswashed with water, dried over Na₂CO₃ and filtered. AcOH (1.0 mL) wasadded to the filtrate. Crystals were formed upon cooling. The crystalswere collected, washed with ethyl ether, and dried in vacuum to give2.45 g (41%) of the title product: mp 108-109° C. Anal.(C₁₅H₁₈BrN₅O₂.CH₃COOH) C, H, N.

Example 189

[0893] 5-Methyl-2-(1-piperazinyl)-3-[2-(3-pyridinyloxy)ethoxy]pyrazine.

[0894] Step 1: tert-Butyl4-{5-bromo-3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}-1-30piperaiziniecarboxylate.

[0895] To a solution of the free base of the product obtained in Example188. Step 2, (0.70 g, 10.85 mmol) in EtOAc (10 mL) and Et₃N (2 mL) wasadded (t-BuOC)₂O (0.46 g. 2.0 mmol). The mixture was stirred at roomtemperature overnight. The reaction mixture was washed with 2 M aqueousNaOH and brine, dried over Na₂CO₃ and concentrated. The residue waspurified by column chromatography on silica gel, using ethylether/hexane (1:3 to 3:1) as eluent to give 0.64 g (72%) of the titleproduct as an oil. MS m/z 481 (M)⁺.

[0896] Step 2: tert-Butyl4-{-Methyl-3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl})-1-piperazinecarboxylate.

[0897] To a mixture of the product obtained in Step 1 (0.38 g, 0.8 mmol)and NiCl₂(dppp) (0.054 g, 0.10 mmol) in dry THF (3 mL) was addeddropwise 2N dimethylzinc in toluene (0.5 mL, 1 mmol) at room temperatureunder stirring. [The reaction was monitored by TLC on SiO₂ using ethylether/n-hexane (1:1)]. After 4 h, an additional portion (0.3 mL, 0.6mmol) of the dimethylzinc solution was added. The reaction was stirredfor another 2 h and quenched with water (3 mL). The mixture wasextracted with ethyl acetate. The organic extract was washed with brine,dried over Na₂CO₃ and concentrated to give 0.29 g of a yellowish oil.Column chromatography on silica gel, using ethyl ether/n-hexane (1:1 to4:1) as eluent, gave 0.19 g (57%) of the title product as an oil. MS m/z415 (M)⁺. HRMS m/z calcd for C₂₁H₂₉N₅O₄ (M)⁺ 415.2220, found 415.2200.

[0898] Step 3:5-Methyl-2-(1-piperazinyl)-3-[2-(3-pyridinyloxy)ethoxy]pyrazine.

[0899] To a solution of the product obtained in Step 2 (0.507 g, 1.22mmol) in CH₂Cl₂ (3.0 mL) was added TFA (1.5 mL) at 5° C. The solutionwas stirred for 2 h and evaporated to dryness. The residue was dissolvedin water (5 mL) and the solution was basified with 50% aqueous NaOH topH>13 and extracted with EtOAc. The organic extract was dried overNa₂CO₃. Evaporation of the solvent gave 0.51 g of the free base.Attempts to prepare a salt of the free base from oxalic acid, fumaricacid or acetic acid failed. The free base was re-generated [treatmentwith 10% NH₃ aqueous solution, extraction with EtOAc and drying(Na)CO₃)] to give 0.15 g (40%) of the title compound as an oil. MS m/z315 (M). HRMS m/z calcd for C₁₆H₂₁N₅O₂ (M)⁺ 315.1695, found 315.1701.

Example 190

[0900]2-{2-[(3-Methoxy-2-pyrazinyl)oxy]ethoxy}-3-(1-piperazinyl)pyrazine,Maleate.

[0901] Step 1: tert-Butyl4-(3-{2-[(3-Chloro-2-pyrazinyl)oxylethoxy}-2-pyrazinyl)-1-piperazinecarboxylate.

[0902] NaH (50% in mineral oil; 0.153 g, 3.50 mmol) was added to astirred solution of2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.00g, 3.08 mmol; prepared in Example 52, Step 2) and 2,3-dichloropyrazine(1.0 g, 6.71 mmol) in dioxane (10 mL). The reaction was stirred in asealed tube at 100° C. overnight. The reaction mixture was poured intowater and extracted with diethyl ether. The ether phase was dried(MgSO₄), concentrated and purified by column chromatography on silicausing toluene/EtOAc (7:3) as eluent to give 0.823 g (61%) of the titleproduct: Pos-EI-MS shows M⁺ and 14 ions supporting the stated structure.HRMS m/z calcd for C₁₉H₂₅ClN₆O₄ (M)⁺ 436.1626, found 436.1606.

[0903] Step 2: tert-Butyl4-(3-{2-[(3-methoxy-2-pyrazinyl)oxy]ethoxy}-2-pyrazinyl)-1-piperazinecarboxylate.

[0904] NaH (50% in mineral oil; 0.010 g, 2.1 mmol) was added to astirred solution of the product from Step 1 (0.38 g, 0.87 mmol) indioxane (8 mL) and MeOH (2 mL) in a reaction tube. As the gas evolutionhad ceased, the tube was sealed and the mixture was stirred at 100° C.for 15 min. The reaction was poured into water and extracted withtoluene, dried (MgSO₄) and concentrated. The residue was purified bycolumn chromatography on silica using toluene/EtOAc (7:3) as eluent togive 0.178 g (47%) of the title product. Pos-EI-MS shows M⁺ and 11 ionssupporting the stated structure. HRMS m/z calcd for C₂₀H₂₈N₆O₅ (M)⁺432.2121, found 432.2126.

[0905] Step 3:2-{2-[(3-Methoxy-2-pyrazinyl)oxy]ethoxy}-3-(1-piperazinyl)pyrazine,Maleate.

[0906] The product from Step 2 (0.175 g. 0.40 mmol) was treated withCH₂Cl₂/TFA/H₂O (50:45:5: 10 mL) for 30 min at room temperature, pouredinto 0.1 M aqueous HCl, and washed with toluene (×2). The aqueous phasewas alkalinized to pH 11 with NaOH, and extracted with diethyl ether(×3). The organic layers were dried (MgSO₄) and concentrated to give0.120 g (0.36 mmol) of the free base of the title product. Maleic acid(0.042 g. 0.36 mmol) in dioxane (0.5 mL) was added to a solution of thefree base in dioxane (3 mL) and left to crystallize to give 0.147 g(82%) of the title product. Pos-EI-MS shows N4+ and 11 ions supportingthe stated structure. HRMS m/z calcd for C₁₅H₂₀N₆O₃ (M)⁺ 332.1597, found332.1607.

Example 191

[0907]2-{2-[(2-Methoxy-3-pyridinyl)oxy]ethoxy}-3-(1-piperazinyl)pyrazine,Fumarate.

[0908] Step 1: 2-Bromo-3-(2-hydroxyethoxy)pyridine.

[0909] The title compound was prepared from 2-bromo-3-hydroxypyridineaccording to the procedure described in Example 91, Step 1. Oil; yield2.33 g (76%).

[0910] Step 2: 3-(2-Hydroxyethoxy)-2-methoxypyridine.

[0911] A mixture of the product obtained in Step 1 (2.33 g, 10.7 mmol)and NaOMe (0.634 mg, 11.8 mmol) in MeOH (50 mL) was refluxed overnight.The reaction mixture was filtered and concentrated. The residue waspurified by column chromatography on silica, using CH₂Cl₂/MeOH/heptane(4:1:5) as eluent, to give 0.81 g (45%) of the title compound as acolorless oil.

[0912] Step 3:2-{2-[(2-Methoxy-3-pyridinyl)oxy]ethoxy}-3-(1-piperazinyl)pyrazine,Fumarate.

[0913] 2-Chloro-3-(1-piperazinyl)pyrazine (0.454 g. 2.13 mmol; fromExample 90, Step 1) was added to a mixture of the product obtained inStep 2 (0.380 g, 2.25 mmol) and NaOt-Bu (0.432 g 4.50 mmol) in dioxane(25 mL). The reaction mixture was stirred at 90° C. for 2 h and thenquenched by adding MeOH (0.6 mL, 13.3 mmol). Silica gel was added andthe mixture was filtered and concentrated in vacuo. The residue waspurified by column chromatography using CHCl₃/MeOH/heptane (4:1:5)containing 0.2% aqueous NH₃ as eluent to give 0.257 g (40%) of the freebase of the title compound as a colorless oil. The flee base % vasdissolved in MeOH (3 mL) and converted into its fumarate salt by addingfumaric acid (0.104 g, 0.87 mmol) in MeOH (3 mL) followed by addition ofether to obtain 0.214 g (56%) of the title compound as white needles: mp181-183° C.; Anal. (C₂₀H₂₅N₅O₇) C, H, N.

Example 192

[0914](2R)-t-(3-{2-[(2-Methoxy-3-pyridinyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine,Fumarate.

[0915] Step 1: (R)-3-Methyl-1-tritylpiperazine.

[0916] (2R)-Methylpiperazine-L-(+)-tartrate* (300 g, 1.2 mmol) was addedto a hot stirred solution of KOH (240 g, 4.3 mol) in H₂O (240 mL). Twophases were formed and the mixture was cooled to room temperature andextracted with CH₂Cl₂ (3×400 mL). The extracts were dried over K₂CO₃ andfiltered. Trityl chloride (260 g, 0.93 mol) was slowly added to awell-stirred solution of the generated (R)-2-metyhylpiperazine* inCH₂Cl₂ under cooling (exotermic). After 45 min, the solution was pouredinto a solution of K₂CO₃ (140 g, 10.00 mol) in water (500 mL). Theresulting organic phase was separated and dried over K₂CO₃, and thesolvent was evaporated. This gave 370 g of the title product as an oil,which was used without purification.

[0917] Step 2: (2R)-1-(3-Chloro-2-pyrazinyl)-2-methylpiperazine.

[0918] A mixture of the product obtained in Step 1 above,2,3-dichloropyrazine (154 g, 1.00 mol) and K₂CO₃ (160 g, 1.20 mol) inDMF (1 L) was heated at 110° C. for 20 h with vigorous stirring. (TLCmonitoring system: CHCl₃: EtOH (20:1); silica). The mixture as cooledand poured slowly into water (6 L) with stirring. The solid wascollected, washed with water, dried, dissolved in CHCl₃ (1 L), dilutedwith n-heptane (1 L), and filtered through SiO₂. Solvents wereevaporated off. The resulting oil was dried under vacuum (3 mm/50° C.,30 min) to remove the DMF. The oil was dissolved in hot ethanol (1 L),and HCl (10% aqueous solution, 300 mL) was added slowly. Trityl carbinolbegan to crystallize out after 10 min. After 30 min the formed tritylcarbinol was filtered off and the ethanol was evaporated. The aqueoussolution was extracted by ether (2×200 mL) and made basic by addition ofK₂CO₃ to pH 12. The alkaline layer was extracted with CHCl₃ (3×200 mL).The combined organic layers were dried (K₂CO₃) and concentrated to give140 g (66%) of the title compound.

[0919] Step 3:(2R)-1-(3-{2-[(2-Methoxy-3-pyridinyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine,Fumarate

[0920] The product obtained in Step 2 (0.494 g, 2.18 mmol) was added toa solution of 3-(2-hydroxyethoxy)-2-methoxypyridine (0.410 g, 2.42 mmol;from Example 191, Step 2) and NaOt-Bu (0.349 g, 3.63 mmol) in dioxane(25 mL) at 90° C. The reaction mixture was stirred at 90° C. for 2 h andthen quenched by adding MeOH (0.6 mL, 13.3 mmol). Silica gel was addedand the mixture was filtered and concentrated in vacuo. The residue waspurified by column chromatography on silica using CHCl₃/MeOH/n-heptane(4:1:5) containing 0.2% aqueous NH₃ as eluent to give 0.382 g (45%) ofthe free base of the title compound as a colorless oil. Part of the freebase (0.150 g, 0.48 mmol) was converted to its fumarate salt to give0.061 g (28%) of the title compound: mp 141-143° C. Anal.(C₂₁H₂₇N₅O₇.0.25H₂O) C, H, N.

Example 193

[0921]2-{2-[(2-Chloro-3-pyridinyl)oxy]ethoxy}-3-(1-piperazinyl)pyrazine,Fumarate.

[0922] Step 1: 2-[(2-Chloro-3-pyridinyl)oxy]ethanol.

[0923] The title compound was prepared from 2-chloro-3-hydroxypyridineaccording to the procedure described in Example 91, Step 1. Oil; yield(77%; purity about 80% according to ¹H NMR). This material was usedwithout further purification in the next synthetic step. HRMS m/z calcdfor C₇H₈ClNO₂ (M)⁺ 173.0240. Found: 173.0244.

[0924] Step 2:2-{2-[(2-Chloro-3-pyridinyl)oxy]etloxy}-3-(1-piperazinyl)pyrazine,Fumarate.

[0925] The title compound was prepared according to the procedure ofExample 90, Step 2, except that the reaction was carried out at roomtemperature, starting from the product obtained in Step 1 above and2-chloro-3-(1-piperazinyl)pyrazine (from Example 90, Step 1). The crudeproduct was purified by column chromatography on silica, usingCHCl₃/MeOH/NH₄O (95:5:0.25, followed by 90:10:0.3) as eluent. The freebase of the title compound was converted to the fumarate salt. Yield41%; mp 200° C. Anal. (C₁₅H₁₈ClN₅O₂.C₄H₄O₄) C, H, N.

Example 194

[0926](2R)-1-(3-{2-[(2-Chloro-3-pyridinyl)oxylethoxy}-2-pyrazinyl)-2-methylpiperazine,Fumarate.

[0927] The title compound was prepared according to the procedure ofExample 192, Step 3, except that the reaction was carried out at roomtemperature and replacing 3-(2-hydroxyethoxy)-2-methoxypyridine with2-[(2-chloro-3-pyridinyl)oxy]ethanol (obtained in Example 193, Step1).The crude product was purified by column chromatography on silica,using CHCl₃/MeOH/NH₄OH (97:3:0.2, followed by 95:5:0.25) as eluent. Thefree base of the title compound was converted to the fumarate salt:yield 25%; mp 147° C. Anal. (C₁₆H₂₀ClN₅O₂.C₄H₄O₄) C, H, N.

Example 195

[0928] 2-{2-[(2-Bromo-3-pyridinyl)oxy]ethoxy}-3-(1-piperazinyl)pyrazine, Fumarate.

[0929] The title compound was prepared according to the procedure ofExample 90, Step 2, except that the reaction was carried out at roomtemperature, starting from 2-bromo-3-(2-hydroxyethoxy)pyridine (obtainedin Example 191, Step 1) and 2-chloro-3-(1-piperazinyl)pyrazine (fromExample 90, Step 1). Yield 39%; mp 202° C. Anal. (C₁₅H₁₈BrN₅O₂)* C₄H₄O₄)C, H, N.

Example 196

[0930](2R)-1-(3-(2-[(2-Bromo-3-pyridinyl)oxy]ethoxy)-2-pyrazinyl)-2-methylpiperazine,Fumarate.

[0931] The title compound was prepared according to the procedure ofExample 192, Step 3, except that the reaction was carried out at roomtemperature, starting from 2-bromo-3-(2-hydroxyethoxy)pyridine (obtainedin Example 191, Step 1) and(2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine (from Example 192. Step2). Yield 23%: mp 154° C. Anal. (C₁₆H₂₀BrN₅O₂).C₄H₄O₄) C, H, N.

Example 197

[0932]2-(2-{[2-(Methylsulfanyl)-3-pyridinyl]oxy}ethoxy)-3-(1-piperazinyl)pyrazine,Fumarate.

[0933] Step 1: 2-{[2-(Methylsulfanyl)-3-pyridinyl]oxy}ethanol.

[0934] To a suspension of sodium thiomethoxide (3.01 g, 42.9 mmol) indry DMF (30 mL) was 2-[(2-chloro-3-pyridinyl)oxy]ethanol (7.82 g, 45.1mmol, from Example 193, Step 1) added and the reaction mixture wasstirred at ambient temperature for 1 h. The solvent was removed underreduced pressure and the residue was partitioned between brine/1 Maqueous NaOH and CHCl₃. The aqueous phase was extracted with anadditional portion of CHCl₃ and the combined organic layers were dried(MgSO₄) and concentrated. The resulting red oil was purified by columnchromatography on silica using toluene/Et₃N/MeOH (96:2:2) as eluent togive 3.0 g (36%) of the title compound as brownish crystals: mp 80° C.Anal. (C₇H₁₁NO₂S) C, H, N.

[0935] Step 2:2-(2-{[2-(Methylsulfanyl)-3-pyridinyl]oxy}ethoxy)-3-(1-piperazinyl)pyrazine,Fumarate.

[0936] The title compound was prepared according to the procedure ofExample 90, Step 2, starting from from2-chloro-3-(1-piperazinyl)pyrazine (from Example 90, Step 1) and theproduct obtained in Step 1 above. The free base of the title compoundwas converted to its fumarate salt: yield 47%; mp 201° C. Anal.(C₁₆H₂₁N₅O₂S C₄H₄O₄) C, H, N.

Example 198

[0937](2R)-2-Methyl-1-[3-(2-{[2-(methylsulfanyl)-3-pyridinyl]oxy}ethoxy)-2-pyrazinyl]piperazine,Fumarate.

[0938] The title compound was prepared according to the procedure ofExample 192. Step 3, starting from(2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine (from Example 192, Step2) and the product of Example 197, Step 1. The free base of the titlecompound was converted to the fumarate salt: yield 39%: mp 179° C. Anal.(C₁₇H₂₃N₅O₂S.C₄]-1₄O₄) C, H, N.

Example 199

[0939]2-[2-[(2-Ethoxy-3-pyridinyl)oxy]ethoxy)-3-(1-piperazinyl)pyrazine,Fumarate.

[0940] Step 1:2-Bromo-3-(2-{]tert-butyl(dimethyl)silyl]oxy}ethoxy)pyridine.

[0941] A solution of dimethyl-1-butylsilyl chloride (11.1 g, 74 mmol) inDMF (30 mL) was added to a suspension of2-bromo-3-(2-hydroxyethoxy)pyridine (15.3 g, 70 mmol; obtained inExample 191, Step 1) and imidazole (10.0 g, 147 mmol) in DMF (30 mL).The reaction mixture was stirred at ambient temperature for 2 h, dilutedwith 0.5 M aqueous NaOH (0.7 L), and extracted twice with toluene. Thecombined organic phases were washed once with water, dried (MgSO₄), andconcentrated. The resulting oil was treated with a mixture of petroleumether and ethyl acetate (95:5; 50 mL) and an analytical sample of whitecrystals was collected. The remaining crystals were mixed with thefiltrate, the solvent was evaporated and the resulting crude product wasused directly in the next step. Solid; yield 18.3 g (78%); mp 81° C.Anal. (C₁₃H₂₂BrNO₂Si) C, H, N.

[0942] Step 2: 2-[(2-Ethoxy-3-pyridinyl)oxy]ethanol.

[0943] The product obtained in Step 1 above (13.2 g, 39.7 mmol) wasadded to sodium ethoxide in EtOH [prepared from Na (10.5 g, 457 mmol)and EtOH (200 mL)]. The resulting mixture was heated at 70° C.overnight. After cooling to ambient temperature, the reaction mixturewas diluted with ice water (0.8 L) and extracted with EtOAc (×4); Thecombined organic phases were washed twice with brine, dried (MgSO₄) andconcentrated. The resulting dark red oil was purified by columnchromatography on silica using toluene/Et₃N (95:5), followed by (90:10),as eluent to give 3.0 g (41%) of the title product as a red oil. HRMSm/z calcd for C₉H₁₃NO₃ (M)⁺ 183.0896. Found: 183.0895.

[0944] Step 3:2-{2-[(2-Ethoxy-3-pyridinyl)oxy]ethoxy}-3-(1-piperazinyl)pyrazine,Fumarate.

[0945] The title compound as prepared according to the procedure ofExample 90, Step 9, starting from 2-chloro-3-(1-piperazinyl)pyrazine(from Example 90, Step 1) and the product obtained in Step 2 above. Thefree base of vile title compound was converted to its fumarate salt:yield 30%; mp 186° C. Anal. (C₁₇H₂₃N₅O₃* C₄H₄O₄) C, H, N.

Example 200

[0946](2R)-1-(3-{2-[(2-Ethoxy-3-pyridinyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine,Fumarate.

[0947] The title compound was prepared according to the procedure ofExample 192, Step 3, starting from(2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine (from Example 192, Step2) and 2-[(2-ethoxy-3-pyridinyl)oxy]ethanol (from Example 199, Step 2).The free base of the, title compound was converted to its fumarate salt:yield 17%; mp 179° C. Anal. (C₁₈H₂₅N₅O₃.C₄H₄O₄) C, H, N.

Example 201

[0948] 5-Ethoxy-3-pyridinyl2-({3-[(2R)-2-methylpiperazinyl]-2-pyrazinyl}oxy)ethyl ether, Fumarate.

[0949] Step 1: 2-[(5-Ethoxy-3-pyridinyl)oxy]-1-ethanol.

[0950] The title compound was prepared according to the procedure ofExample 91, Step 1, starting from 5-ethoxy-3-pyridinol (1.0 g, 7.2mmol). Yield: 1.23 g (93%). MS m/z 184 (M+H)⁺.

[0951] Step 2: 5-Ethoxy-3-pyridinyl2-({3-[(2R)-2-methylpiperazinyl]-2-pyrazinyl}oxy)ethyl ether, Fumarate.

[0952] To a stirred solution of the product obtained in Step 1 (660 mg,3.60 mmol) in dioxane (6 mL) was added K-1-BuO (438 mg, 3.90 mmol).After 15 min, (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine (638 mg,3.0 mmol; from Example 192, Step 2) was added and the solution wasstirred at 85° C. for 2 h. After cooling, CHCl₃ was added and themixture filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel using CH₂Cl₂/methanol (9:1) as eluent togive the free base of the title compound (0.60 g. 56%). The free basewas converted to the hydrochloride salt: yield 0.53 g (37%); mp.101-104° C.; MS m/z 360 (M+1i). HRMS m/z calcd for C₁₈H₂₅N₅O₃ (M)⁺3590.1957, found 359.1943.

Example 202

[0953] 3-[(2R)-2-Methylpiperazinyl]-2-pyrazinyl2-(5-pyrimidinyloxy)ethyl ether, Fumarate.

[0954] The title product was prepared according to the procedure ofExample 201, Step 2, starting from 2-(5-pyrimidinyloxy)-1-ethanol (505mg, 3.60 mmol; from Example 166, Step 1) and(2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine (638 mg, 3.00 mmol;from Example 192, Step 2). The residue was purified by columnchromatography on silica gel using CH₂Cl₂/methanol (9:1) as eluent togive 456 mg (48%) of the free base of the title compound. The free basewas converted to the hydrochloride: mp. 145-147° C.; MS m/z 317 (M+H)⁺.Anal. (C₁₅H₂₀N₆O₂ 1.3 C₄H₄O₄) C, H, N.

Example 203

[0955] Step 1: 2-[(6-Chloro-3-pyridinyl)oxy]-1-ethanol.

[0956] The title compound was prepared according to the procedure ofExample 91, Step 1, starting from 2-chloro-5-hydroxypyridine. Solid;yield 78%. MS m/z 173 (M)⁺. Anal. (C₇H₈ClNO₂) C, H, N.

[0957] Step 2:2-{2-[(6-Chloro-3-pyridinyl)oxy]ethoxy}-3-(1-piperazinyl)pyrazine,Maleate.

[0958] The title compound was prepared according to the procedure ofExample 90, Step 2, starting from the product obtained in Step 1 above.The crude product was purified by column chromatography (gradient:EtOAc/MeOH (90:10)+1% NH₃ to EtOAc/MeOH (80:20)+1% NH₃) on silica togive 22% of the free base of the title compound as a colorless oil. Partof this material as converted to its maleate salt: mp 145.9-146.3° C.;MS m/z 336 (M+H)⁻. Anal. (C₁₅H₁₈ClN₅O, C₄H₄O₄) C, H, N.

Example 204

[0959]2-{2-[(6-Methoxy-3-pyridinyl)oxy]ethoxy}-3-(1-piperazinyl)pyrazine,Maleate.

[0960] Step 1: 2-[(6-Methoxy-3-pryidinyl)oxy]-1-ethanol.

[0961] A mixture of the product of Example 203. Step 1 (513 ml 2.96mmol) and freshly prepared NaOMe (3.06 g, 56.6 mmol) in dry dioxane (25mL) was heated in a sealed Pyrex tube at 130° C. for 24 h. The solventwas evaporated under reduced pressure and the residue was dissolved inCH₂Cl₂. The organic phase was washed with brine, dried (MgSO₄), andconcentrated to give the crude product as an oil (430 mg). Purificationby column chromatography, using isohexane/EtOAc (1:1) as an eluent, gavethe title product as a white solid. Yield 258 mg (51%); MS m/z 169 (M)⁺.Anal. (C₈H₁₁NO₃) C, H, N.

[0962] Step 2:2-{2-[(6-Methoxy-3-pyridinyl)oxy]ethoxy}-3-(1-piperazinyl)pyrazine,Maleate.

[0963] The title compound was prepared according to the procedure ofExample 90, Step 2, starting from the product obtained in Step 1 above.Yield of free base of the title product 90%. Part of this material wasconverted to its maleate salt: mp 151.8-152.6° C.; MS m/z 332 (M+H)⁺.Anal. (C₁₆H₂₁N₅O₃ C₄H₄O₄) C, H, N.

Example 205

[0964]4-Methoxy-N/,N-dimethyl-3-[2-({3-[(2R)-2-methylpiperazinyl]-2-pyrazinyl}oxy)ethoxy]aniline,Fumarate.

[0965] Step 1: 5-(Dimethylamino)-2-methoxyphenol.

[0966] To a stirred solution of 5-amino-2-methoxyphenol (5.0 g, 36 mmol)in ethanol (250 mL), was added 33% formaldehyde (4×1.5 mL at times 0, 60min, 140 min and 185 min) and sodium cyanoborohydride (4×0.8 g, at times30 min, 120 min, 165 min and 210 min). After each addition of thehydride, pH was adjusted to 6 using acetic acid. The mixture was stirredfor an additional 2 h and then concentrated in vacuo. The residue waspartitioned between brine/diethyl ether and the organic phase was driedand concentrated. The residue was purified by column chromatography onsilica gel using hexane/EtOAc (7:3) as eluent to give 1.17 g (20%) ofthe title compound. MS m/z 168 (M+H).

[0967] Step 2: 2-15-(Dimethylamino)-2-niethoxyplienioxy]-1-ethanol.

[0968] The title compound was prepared according to the procedure ofExample 91. Step 1, starting from 5-(dimethylamino)-2-methoxyphenol(1.17 g, 7.0 mmol; from Step 1 above): Yield: 1.44 g (97%).

[0969] Step 3:4-Methoxy-N,N-dimethyl-3-[2-({3-[(2R)-2-methylpiperazinyl]-2-pyrazinyl}oxy)ethoxy]aniline,Fumarate.

[0970] The title product was prepared according to the procedure ofExample 192, Step 3, starting from the product obtained in Step 2 above(700 mg, 3.30 mmol) and (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine(585 mg, 2.75 mmol; from Example 192, Step 2). The crude product waspurified by column chromatography on silica gel using CH₂Cl₂/CH₃OH (9:1)as eluent to give the free base of the title compound. The free base wasconverted to the fumaric acid salt. Yield: 135 mg (10% over all); mp.147-149° C.; MS m/z 388 (M+H)⁺. Anal. (C₂₀H₂₉N₅O₃ C₄H₄O₄) C, H, N.

Example 206

[0971](2R)-Methyl-1-[3-(2,5-dimethoxyphenoxyethoxy)-2-pyrazinyl]piperazine,Maleate. Maleate

[0972] Step 1: 2-(2,5-Dimethoxyphenoxy)-1-ethanol*.

[0973] The title compound was prepared according to the procedure ofExample 91, Step 1, starting from 2,5-dimethoxyphenol.** Yield 85%; mp50-52° C. Anal (C₁₀H₁₄O₄) C, H.

[0974] Step 2:(2R)-Methyl-1-[3-(2,5-dimethoxyphenoxyethoxy)-2-pyrazinyl]piperazine,Maleate.

[0975] The title product was prepared according to the procedure ofExample 192. Step 3, starting from the product obtained in Step 1 aboveand (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine (from Example 192,Step 2). Yield 26%; mp 105-109° C. Anal (C₁₉H₂₆N₄O₄.C₄H₄O₄) C, H, N.

Example 207

[0976] 3-(1-Piperazinyl)-2-pyrazinyl1,2,3,4-tetrahydro-2-naphthalenylmethyl ether, Fumarate.

[0977] The title product was prepared according to the procedure ofExample 90, Step 2, starting from1,2,3,4-tetrahydro-naphtalenylmethanol* (0.79 g, 4.88 mmol) and2-chloro-3-(1-piperazinyl)pyrazine (0.99 g, 4.6 mmol; from Example 90,Step 1). Oil; yield 57% of the free base. The free base was converted tothe fumarate: mp 186-188° C.; Anal. (C₁₉H₂₄N₄O C₄H₄O₄.0.25H₂O) C, H, N.

Example 208

[0978] 3-[(2R)-2-methylpiperazinyl]-2-pyrazinyl1,2,3,4-tetrahydro-2-naphthalenylmethyl ether, Fumarate.

[0979] The title product was prepared according to the procedure ofExample 192, Step 3, starting from1,2,3,4-tetrahydro-naphtalenylmethanol (0.98 g, 6.04 mmol) and(2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine (1.3 g, 5.7 mmol; fromExample 192, Step 2). The product was isolated as a mixture of twodiastereomers. Yield of the free base was 63%. The free base wasconverted to the fumarate salt: mp 169-172° C. Anal (C₂₀H₂₆N₄O C₄H₄O₄)C, H, N.

Example 209

[0980] 1-{4-[2-(3-Pyridinyloxy)ethoxy]-1,2,5-thiadiazol-3-yl}piperazine,Maleate.

[0981] Step 1: 3-Chloro-4-(1-piperazinyl)-1,2,5-thiadiazole,Hydrochloride.

[0982] A mixture of 3,4-dichloro-1,2,5-thiadiazole (4.00 g, 25.8 mmol)and piperazine hexahydrate (25.0 g, 130 mmol) in DMF (25 mL) was heatedat 70° C. for 20 minutes. After cooling to ambient temperature, thereaction mixture was basified (11M NaOH) and brine was added. Theresulting mixture was extracted with CHCl₃ (×3). The combined organicphases were washed twice with brine/water (1:1), dried (MgSO₄) and thesolvent was evaporated. The resulting oil was purified by columnchromatography on silica gel using CHCl₃ as eluent to give 2.77 g (52%)of the title compound as a colourless oil Which was converted to itshydrochloride salt: mp 231° C. (dec). Anal. (C₆H₉CIN₄S.HCl), C calc29.89, found 30).4, H, N.

[0983] Step 2:1-{4-[2-(3-Pyridinyloxy)ethoxy]-1,2,5-tetradiazol-3-yl}piperazine,Maleate.

[0984] The product from Step 1 above (0.70 g, 3.42 mmol),2-(3-pyridinyloxy)-1-ethanol (0.57 g, 4.10 mmol; from Example 150,Step 1) and sodium hydride (60% in mineral oil, 0.19 g, 4.79 mmol) wasstirred at 70° C. in dioxane for 14 h. The reaction mixture was filteredthrough a pad of silica gel and concentrated. The remaining oil waspurified by by C-18 HPLC using CH₃CN/H₂O (gradient: CH₃CN 0% to 100%).This furnished the free base of the title compound as an oil which wasconverted to the maleate salt: yield 0.16 g (11%); mp 116-118° C. Anal.(C₁₃H₁₇N₅O₂S C₄H₄O₄) C, H, N.

Example 210

[0985]2-[2-(2,3-Dihydro-1,4-benzodioxin-6-yloxy)ethoxy]-3-(1-piperazinyl)pyrazine,Dihydrochloride

[0986] Step 1: 2-(2,3-Dihydro-1,4-benzodioxin-6-yloxy)ethanol.

[0987] The title compound was prepared according to the proceduredescribed in Example 91, Step 1 starting from6-hydroxy-1,4-benzodioxane.* Oil; yield 55%. MS m/z 196 (M)⁺. HRMS m/zcalcd for C₁₀H₁₂O₄ (M)⁺ 196.0736, found 196.0735.

[0988] Step 2: tert-butyl4-{3-[2-(2,3-Dihydro-1,4-benzodioxin-6-yloxy)ethoxy]-2-pyrazinyl}-1-piperazinecarboxylate.

[0989] To a solution of the product obtained in Step 1 (0.22 g, 1.12mmol) and 2-chloro-3-(1-piperazinyl)pyrazine (0.25 g, 1.26 mmol; fromExample 90, Step 1) in dioxane (5 mL) was added NaH (50% in mineral oil,0.05 g, 11.1 mmol). The solution was heated at 90° C. overnight. Aftercooling, EtOAc (10 mL) was added and the solution was washed With water,dried over Na₂CO₃ and concentrated. The oily residue (0.51 g) wasdissolved in a mixture of EtOAc (2 mL) and Et₃N (1 mL) and (t-BuOC)₂O(0.32 g, 1.5 mmol) was added. The resulting mixture was stirred at roomtemperature overnight. The reaction mixture was concentrated and theresidue was purified by column chromatography on silica gel usingMeOH/EtOAc (2:1) as eluent to give 0.43 g (93%) of the title product asan oil. MS m/z 458 (M4)”. HRMS m/z calcd for C₂₃H₃₀N₄O₆ (M)⁺ 458.2165,found 458.2178.

[0990] Step 3:2-[2-(2,3-Dihydro-1,4-benzodioxin-6-yloxy)ethoxy]-3-(1-piperazinyl)pyrazine,Dihydrochloride.

[0991] To a solution of the product obtained in Step 2 (0.43 g, 0.94mmol) in CH₂Cl₂ (2 mL) was added CF₃COOH (1.5 mL) at room temperature.The solution was stirred at room temperature for 5 h and evaporated todryness. The residue was dissolved in EtOAc. The solution was washedwith 25% aqueous NaOH and dried over K₂CO₃. A solution of HCl in Et₂Owas dropped into the solution until no more precipitate formed. Theprecipitate was collected, washed with ethyl ether, and dried in vacuumto give 251 mg (62%) of the title product: mp 158-160° C. MS m/z 358(M)⁺. HRMS m/z calcd for C₁₈H₂₂N₄O₄ (M)⁺ 358.1641, found 358.1647.

Example 211

[0992] 2-[3-(2-Methoxyphenyl)propoxy]-3-(1-piperazinyl)pyrazine,Maleate.

[0993] A mixture of 2-chloro-3-(1-piperazinyl)pyrazine (0.40 g, 2.0mmol; from Example 90 Step 1), 3-(2-methoxyphenyl)-propan-1-ol (0.50 g,3.0 mmol), and KO-t-Bu (1 M in t-BuOH; 3 mL, 3 mmol) in dry dioxane (30mL) was stirred at reflux for 20 h. The reaction was quenched byaddition of water (2 mL). The solvent was evaporated and the crudemixture was passed through a column of hydromatrix material with CH₂Cl₂as eluent. The elute was concentrated and the remaining oil was purifiedby silica gel chromatography using EtOAc/MeOH/Et₃N (8:1:1) as eluent.This furnished the free base of the title compound as an oil which wasconverted to the maleate salt: yield 0.20 g (22%); mp 132-133° C. Anal.(C₁₉H₂₄N₄O₂.C₄H₄O₄) C, H, N.

Example 212

[0994]2-{[(2E)-3-(2-Methoxyphenyl)-2-propenyl]oxy}-3-(1-piperazinyl)pyrazine,Maleate.

[0995] The title compound was prepared according to the procedure ofExample 90, Step 2, starting from 2-chloro-3-(1-piperazinyl)pyrazine(0.50 g, 2.5 mmol, from Example 90. Step 1) and 2-methoxy-cinnamylalcohol (0.54 g, 3.3 mmol).

[0996] Yield 0.45 g (41%); mp 136° C. (dec). Anal. (C₁₈H₂₂N₄O₂.C₄H₄O₄)C, H, N.

Example 213

[0997] 3-(1-piperazinyl)-2-pyrazinyl 6-quinolinylmethyl ether, Fumarate.

[0998] The title compound was prepared according to the procedure ofExample 90, Step 2, starting from 2-chloro-3-(1-piperazinyl)pyrazine(1.2 g, 5.6 mmol, from Example 90, Step 1) and 6-quinolinemethanol*(0.89 g, 5.6 mmol). Yield 0.80 g (94%); mp 207-209° C. Anal. (C₁₈H₁₉N₅OC₄H₄O₄.25H₂O)C, H, N.

Example 214

[0999]N,N′-Dimethyl-N-[3-(2-phenoxyethoxy)-2-pyrazinyl]-1,2-ethanediamine.

[1000] A mixture of 2-chloro-3-(2-phenoxyethoxy)pyrazine (50 mg, 0.20mmol; from Example 1, Step 1) and N,N′-dimethylethylenediamine (0.2 mL,1.9 mmol) was heated in a MicroWell 10 microwave reactor for 6 min at100W. The reaction mixture was partitioned between water and EtOAc andapplied to a hydromatrix column. The column was eluted with EtOAc andthe elute was concentrated. The product was purified by AmberchromCG-161m LC using CH₃CN/H₂O (gradient: CH₃CN 0% to 100%). Yield 2 mg(4%). MS m/z 303 (M+H)⁺.

Example 215

[1001]N,N-Dimethyl-2-{[3-(2-phenoxyethoxy)-2-pyrazinyl]sulfanyl}ethanamine.

[1002] A mixture of 2-chloro-3-(2-phenoxyethoxy)pyrazine (100 mg, 0.40mmol, from Example 1, Step 1), dimethylaminoethanethiol hydrochloride(56 mg, 0.40 mmol) and sodium hydride (60% in mineral oil; 32 mg. 0.80mmol) was stirred at 60° C. for 12 h. The reaction mixture wasconcentrated and partitioned between water and EtOAc and applied on ahydromatrix column. The column was eluted with EtOAc and the elute wasconcentrated. The product was purified by Amberchrom CG-161m LC usingCH₃CN/H₂O (gradient: CH₃CN 0% to 100%). Yield 24 mL (24%). MS m/z 320(M+)⁺.

Example 216

[1003](2R)-Methyl-1-(3-(2-[(1-oxido-3-pyridinyl)oxy]ethoxy}-2-pyrazinyl)piperazine.

[1004] Step 1: tert-Butyl(3R)-3-methyl-4-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}-1-piperazinecarboxylate.

[1005] Di-tert-butyl dicarbonate (1.01 g, 4.64 mmol) in dioxane (50 mL)was added to a solution of the fumararate salt of(2R)-methyl-1-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine* (2.0g, 4.64 mmol) in a mixture of dioxane/10% aqueous NaHCO₃ (1:1; 100 mL).The reaction mixture was stirred overnight at room temperature andextracted with EtOAc (3×100 mL). The organic phase was concentrated andthe residue purified by column chromatography on silica usingisohexane/EtOAc (3:1 to 1:1) as eluent. This furnished 1.48 g (77%) ofthe title product as an oil. MS m/z 416 (M+H)⁺. HRMS m/z calcd forC₂₁H₂₉N₅O₄ (M)⁺ 415.2220 found 415.2224.

[1006] Step 2: tert-Butyl(3R)-methyl-4-(3-{2-[(1-oxido-3-pyridinyl)oxy]ethoxy}-2-pyrazinyl)-1-piperazinecarboxylate.

[1007] MCPBA (2.91 g, 16.9 mmol) was added to the solution of theproduct obtained in Step 1 above (1.4 g, 3.37 mmol) in CH₂Cl₂ (50 mL).The reaction mixture was stirred for 1 h at room temperature. This gavea mixture of two unknown di-oxidized derivatives (MS). Aqueous sodiummetabisulfite (10%, 50 mL) was added and the reaction mixture wasstirred at room temperature until the di-oxidized products had convertedto a single mono-oxidized derivative. Extraction with EtOAc (3×50 mL),concentration, and purification of the residue by column chromatographyon silica, using isohexane/EtOAc (3:1 to 1:1) as eluent, furnished 0.96g (66%) of the title product as an oil. MS m/z 432 (M+H)⁺. HRMS m/zcalcd for C₂₁H₂₉N₅O₅ (M)⁺ 431.2169, found 431.2171.

[1008] Step 3:(2R)-2-Methyl-1-(3-{2-[(1-oxido-3-pyridinyl)oxy]ethoxy}-2-pyrazinyl)piperazine.

[1009] The product obtained in Step 2 (0.86 g, 2.0 mmol) as treated withCH₂Cl₂/TFA (75:25; 10 mL) for 1 h at room temperature. Alterconcentration, the residue as purified by column chromatography onsilica using EtOAc/MeOH/Et₃N (80:15:5) as eluent to give 0.32 g (48%) ofthe title compound as an oil. MS m/z 332 (M+H)⁺. HRMS ml: calcd forC₁₆H₂₁N₅O₃ (M)⁺ 331.1644, found 331.1655.

Example 217

[1010] 2-[(2-Phenoxyethyl)sulfanyl]-3-(1-piperazinyl)pyrazine,Trifluoroacetate.

[1011] Step 1: tert-Butyl4-{3-[(2-hydroxyethyl)sulfanyl]-2-pyrazinyl}-1-piperazinecarboxylate.

[1012] Sodium hydroxide (0.92 g, 23 mmol) was dissolved in water (9 mL)and dioxane (15 mL). 2-Mercaptoethanol (0.54 mL, 7.7 mmol) was addedwhile stirring and2-chloro-3-(4-tert-butoxycarbonyl-1-piperazinyl)pyrazine (2.3 g, 7.7mmol, from Example 52, step 1) in dioxane (10 mL) was added. Thereaction mixture was heated at 100° C. for 22 h. After cooling to roomtemperature, it was extracted with EtOAc. The organic layer was dried(K₂CO₃) and the solvent was removed under reduced pressure. The residuewas purified by chromatography on silica gel using hexane/ EtOAc (1:1)as eluent to give 1.71 g (65%) of the title compound as an orange oil.MS m/z 341 (M+H)⁺.

[1013] Step 2: tert-Butyl4-{3-[(2-phenoxyethyl)sulfanyl]-2-pyrazinyl}-1-piperazinecarboxylate.

[1014] The product obtained in Step 1 (0.135 g, 0.39 mmol),triphenylphosphine (0.134 g, 0.51 mmol) and phenol (48 mg, 0.51 mmol)were dissolved in dry THF (4 mL). Diethyl azodicarboxylate (80 μL, 0.51mmol) was then added dropwise. The reaction mixture was stirred at roomtemperature overnight. The solvent was then removed under reducedpressure. The residue was purified by chromatography on silica gel usinghexane/EtOAc (1:1) follwed by a second column using (CH₂Cl₂ CH₃OH). Thisgave 29 mg (18%) of the title compound as a yellow oil.

[1015] Step 3: 2-[(2-Phenoxyethyl)sulfanyl]-3-(1-piperazinyl)pyrazine,Trifluoroacetate.

[1016] The product obtained in Step 2 (30 mg, 0.072 mmol) was dissolvedin CH₂Cl₂ (0.75 mL) and cooled to −0° C. Trifluoroacetic acid (0.25 mL)was then added and the reaction mixture as stirred for 40 mill at 5° C.The solvent as evaporated under-vacuum. It gave a beige solid 26 nmg ofthe crude product. Purification by reverse phase preparative HPLC on aSymmetryPrep C₁₈ column (150×19 mm, 7 μm), eluting with a gradient of 5%CH₃CN in 95% water to 95% CH₃CN in 5% water (0.2% TFA buffer), of a 13mg sample gave 6 mg (39%) of the title product as a white solid. MS m/z317 (M+H)⁺; HRMS m/z calcd for C₁₆H₂₀N₄OS (M)⁺ 316.1 358 found 316.1355.Anal. (C₁₆H₂₀N₄OS.C₂HF₃O₂.0.5H₂O) C, H, N.

Example 218

[1017]7-(2-{[4-(1-piperazinyl)-1,2,5-thiadiazol-3-yl]oxy}ethoxy)-2H-chromen-2-one.

[1018] Step 1: tert-Butyl4-(4-chloro-1,2,5-thiadiazol-3-yl)-1-piperazinecarboxylate.

[1019] A mixture of N-Boc-piperazine (2.97 g, 15.9 mmol), K₂CO₃ (2.20 g,15.9 mmol) and 3,4-dichloro-1,2,5-thiadiazole (1.5 mL, 15.9 mmol) inCH₃CN (30 mL) was stirred at 100° C. for 19 h and at room temperaturefor 4 days. The reaction mixture was then diluted with EtOAc and water.The organic phase was dried (K₂CO₃) and the solvent was removed underreduced pressure. The residue was purified by chromatography on twosuccessive silica gel columns eluting with hexane/EtOAc (1:1) and (7:3),respectively. This gave 1.54 g (31%) of the title product as a yellowsolid.

[1020] Step 2: tert-Butyl4-[4-(2-hydroxyethoxy)-1,2,5-thiadiazol-3-yl]-1-piperazinecarboxylate.

[1021] K-t-BuO (1.24 g, 11 mmol) was added to a mixture of the productobtained in Step 1 (1.98 g, 6.5 mmol) and ethylene glycol (2.54 ml, 45.5mmol) in pyridine (15 ml). The reaction mixture was stirred at 100° C.for 6 h and at room temperature overnight. The solution was then pouredinto ice-water and diluted with EtOAc. The organic phase was dried(MgSO₄) and the solvent removed under reduced pressure. The residue waspurified by chromatography on silica gel eluting hexane/EtOAc (1:1) togive 1.71 g (65%) of title product as an orange oil. MS mL-331 (M+11)⁺.

[1022] Step 3: tert-Butyl4-(4-{2-[(2-oxo-2H-chromen-7-yl)oxy]ethoxy}-1,2,5-thiadiazol-3-yl)-1-piperazinecarboxylate.

[1023] Diethyl azodicarboxylate (DEAD, 61 μl. 0.39 mmol) was addeddropwise to a mixture of the product obtained in Step 2 (100 mg, 0.30mmol), triphenylphosphine (102 m 0.39 mmol) and 7-hydroxycoumarin (63mg, 0.39 mmol) in dry THF (5 mL). The reaction mixture was stirred atroom temperature for 5 days. After solvent removal, the residue waspurified by chromatography on silica gel eluting with hexane/EtOAc (1:1)to give the title product as a white solid (176 mg) which had low purity(67% by HPLC). This material was used directly in the following stepwithout further purification.

[1024] Step 4:7-(2-{[4-(1-piperazinyl)-1,2,5-thiadiazol-3-yl]oxy}ethoxy)-2H-chromen-2-10one.

[1025] The product obtained in Step 3 (176 mg) was diluted in CH₂Cl₂(1.5 mL) and cooled to ˜0° C. Trifluoroacetic acid (0.5 mL) was addedand the reaction mixture was stirred for 1 h at 5° C. After solventremoval in vacuo, the residue was purified by chromatography on silicagel using hexane/EtOAc (1:1) followed by CH₂Cl₂/MeOH/Et₃N (90:5:5) aseluents This furnished 45 mg (40%) of the title product as a whitesolid. MS m/z 375 (M+H)⁺.

Example 219

[1026] Step 1: tert-Butyl4-{4-[2-(7-isoquinolinyloxy)ethoxy]-1,2,5-thiadiazol-3-yl}-1-piperazinecarboxylate.

[1027] The title compound was prepared according to the procedure ofExample 218, Step 3 starting from the product of Example 218, Step 2(100 mg, 0.30 mmol), triphenylphosphine (102 mg, 0.39 mmol),7-hydroxyisoquinoline (57 mg, 0.39 mmol) and diethyl azodicarboxylate(61 μl, 0.39 mmol) except that the reaction mixture was stirred at roomtemperature for 5 days. It gave an orange oil (0.34 g) of low purity(63% by HPLC). It was used directly in the following step withoutfurther purification.

[1028] Step 2:7-(2-{[4-(1-piperazinyl)-1,2,5-thiadiazol-3-yl]oxy}ethoxy)isoquinoline.

[1029] The product obtained in Step 1 (340 mg) was dissolved in CH₂Cl₂(1.5 mL) and cooled to ˜0° C. Trifluoroacetic acid (0.5 mL) was addedand the reaction mixture was stirred at 5° C. for 1 h. After solventremoval in vacuo, the residue was purified by chromatography on silicagel using hexane/EtOAc (1:1) followed by CH₂Cl₂/CH₃OH/Et₃N (90:5:5) aseluents. This furnished 59 mg (55%) of the title product as a yellowoil. MS m/z (M+H)⁺ 358.

Example 220

[1030]2-{2-[3-(2-Fluoroethoxy)phenoxy]ethoxy}-3-(1-piperazinyl)pyrazine,Trifluoroacetate.

[1031] Step 1: tert-Butyl4-{3-[2-(3-hydroxyphenoxy)ethoxy]-2-pyrazinyl}-1-piperazinecarboxylate.

[1032] To a stirred solution of 2-(3-hydroxyphenoxy)ethanol (7.71 g,0.05 mol) in dry DMF (100 mL) at ˜0° C. (ice bath) was added NaH (3.90g, 0.163 mol) in portions under N₂. When the H₂-evolution had ceased, asolution of 2-chloro-3-(4-tert-butoxycarbonyl-1-piperazinyl)pyrazine(0.05 mol, 14.9 g; from Example 52, Step 1) in dry DMF (70 mL) was addedin one portion. The mixture was stirred at 65° C. for 1.75 h. Aftercooling, the reaction was quenched by addition of H₂O in DMF. Themixture was filtered and concentrated, in vacuo. The residue wasdissolved in EtOAc, washed with 1 M KHSO₄ and water, dried(Na₂SO₄+Norit), and concentrated in vacuo to give the title compound asa beige sticky oil. Yield 94%. This product was used directly in thenext step without 1further purification.

[1033] Step 2:2-{2-[3-(2-Fluoroethoxy)phenox]ethoxy)-3-(1-piperazinyl)pyrazine,Trifluoroacetate.

[1034] The product obtained in Step 1 above (83 mg, 0.20 mmol) wasdissolved in CH₂Cl₂ (8.0 mL) and treated first with polymer supportedtriphenylphosphine (3.0 mmol/g) (133 mg, 0.40 mmol), 2-fluoroethanol (26mg. 0.40 mmol) and then diethyl azodicarboxylate (DEAD; 70 mg. 0.40mmol). The reaction mixture was shaken at room temperature, for 18 h,then filtered to remove the solid support. The filtrate was concentratedunder reduced pressure then diluted with MeOH (1.5 mL) and purified bypreparative C-18 HPLC using CH₃CN/H₂O/TFA (gradient: C₁H₃CN 60% to 90%,TFA 0.1%) to give the Boc-protected intermediate. This material % as notisolated but treated directly with a solution of 25% TEA in CH₂Cl₂ for30 min then concentrated under reduced pressure to afford 24 mg (25%) ofthe title compound. MS m/z 363 (M+H)⁺.

Example 221

[1035]2-(2-{3-[2-(4-Methyl-1,3-thiazol-5-yl)ethoxy]phenoxy}ethoxy)-3-(1-piperazinyl)pyrazine,Trifluoroacetate.

[1036] The title compound was prepared according to the procedure ofExample 220, Step 2, starting from 4-methyl-5-thiazolylethanol (57 mg,0.40 mmol) and the product obtained in Example 220, Step 1, (83 mg, 0.20mmol) to give 57 mg (51%) of the title compound. MS m/z 442 (M+H)⁺.

Example 222

[1037]2-{2-[3-(Cyclopropylmethoxy)phenoxylethoxy}-3-(1-piperazinyl)pyrazine,Trifluoroacetate.

[1038] The title compound was prepared according to the procedure ofExample 220, Step 2, starting from cyclopropylmethanol (29 mg, 0.40mmol) and the product obtained in Example 220, Step 1, (83 mg, 0.20mmol) to give 30 mg (31%) of the title compound. MS m/z 371 (M+H)⁺.

Example 223

[1039] 2-{2-[3-(3-Butenyloxy)phenoxy]ethoxy}-3-(1-piperazinyl)pyrazine,Trifluoroacetate.

[1040] The title compound was prepared according to the procedure ofExample 220, Step 2, starting from 3-buten-1-ol (29 mg, 0.40 mmol) andthe product obtained in Example 220, Step 1 (83 mg, 0.20 mmol) to give57 mg (59%) of the title compound. MS m/z 371 (M+H)⁺.

Example 224

[1041]N,N-Dimethyl-N-(2-[3-(2-([3-(1-piperazinyl)-2-pyrazinyl]oxyethoxy)phenoxy]-ethyl}amine,Trifluoroacetate.

[1042] The title compound was prepared according to the procedure ofExample 220, Step 2, starting from 2-dimethylaminoethanol (36 mg, 0.40mmol) and the product obtained in Example 220, Step 1 (83 mg, 0.20 mmol)to give 37 mg (37%) of the title product. MS (ES+) m/z 388 (M+H)⁺.

Example 225

[1043]2-(1-piperazinyl)-3-{2-[3-(tetrahydro-2H-pyran-4-yloxy)phenoxy]ethoxy}pyrazine,Trifluoroacetate.

[1044] A solution of the product obtained in Example 220, Step 1 (208mg, 0.50 mmol) in CH₂Cl₂ (8.0 mL) was treated first with polymersupported triphenylphosphine (3.0 mmol/g) (200 mg, 0.60 mmol),tetrahydro-4H-pyran-4-ol (51 mg, 0.50 mmol) and then diethylazodicarboxylate (87 mg, 0.50 mmol). The reaction mixture was shaken atroom temperature for 18 h, then filtered to remove the solid support.The filtrate was concentrated under reduced pressure and the residue waspurified by chromatography on silica gel. Elution with CH₂Cl₂/Et₂O(110:1) gave the crude N-Boc-protected intermediate which was furtherpurified by preparative C-18 HPLC using CH₃CN/H₂O/TFA (gradient: CH₃CN60% to 90%, TFA 0.1%). This material was not isolated but treateddirectly with a solution of 25% TFA in CH₂Cl₂ for 30 min thenconcentrated under reduced pressure to afford the title compound 19.0 mg(7%), MS m/z 401 (M+H)⁺.

Example 226

[1045]2-{2-[3-(2-Methoxyethoxy)phenoxy]ethoxy}-3-(1-piperazinyl)pyrazine.

[1046] Step 1: tert-Butyl4-(3-{2-[3-(2-methoxyethoxy)phenoxy]ethoxy}-2-pyrazinyl)-1-piperazinecarboxylate.

[1047] NaH (80% dispersion in mineral oil; 66 mg, 2.75 mmol) was addedto a stirred solution of the product obtained in Example 220, Step 1(716 mg, 1.84 mmol) in dry DMF (10 mL). When the H₂-evolution hadceased, 2-bromoethyl methyl ether (256 mg, 1.84 mmol) was added, and themixture was stirred at 60° C. for 2.5 h. The reaction was quenched byaddition of a mixture of HOAc (0.065 mL) and DMF (0.5 mL) followed by amixture of water (0.065 mL) and DMF (0.50 mL). The resulting mixture wasfiltered, concentrated in vacuo, and the residue was dissolved intoluene. The solution was washed with 1 M aqueous KHSO₄, dried (Na₂SO₄)and concentrated in vacuo to give 0.60 g (69%) of the title compound asan oil which as used in the next step without further purification.

[1048] Step) 2:2-{2-[3-(2-Methoxyethoxy)phenoxy]ethoxy}-3-(1-piperazinyl)pyrazine.

[1049] The product obtained in Step 1 above as dissolved in a mixture ofEtOAc (18 mL) and ether (9 mL) and 5 M HCl/ether (9 mL) was added. Themixture was stirred at room temperature for 3 h. The precipitatatedhydrochloride salt was filtered off and washed thoroughly with ether.The hydrochloride was dissolved in EtOAc/MeOH/Et₃N (100:40:5) andpurified by column chromatography on silica using NH₃-satd. EtOAc/CH₃OH(100:15) as eluent. The combined pure fractions were concentrated invacuo and the resulting oil was dried (08 torr, room temperature) togive 0.36 g (69%) of the title product. HRMS m/z calcd for C₁₉H₂₆N₄O₄(M)⁺ 374.1954, found 374.1947.

Example 227

[1050] 1-{2-[3-(2-([3-(1-piperazinyl)-2-pyrazinyloxy}ethoxy)phenoxy]ethyl)-2-pyrrolidinone.

[1051] Diethyl azodicarboxylate (DEAD; 575 mg, 3.30 mmol), dissolved indry THF (5 mL), was added to a stirred mixture of the compound obtainedin Example 220, Step 1 (983 mg, 2.36 mmol),1-(2-hydroxyethyl)-2-pyrrolidinone (427 mg, 3.30 mmol) and Ph₃P (867 mg,3.30 mmol) in dry THF (50 mL). The reaction mixture was stirred at room1temperature overnight and the solvent was evaporated. The residue wastreated with EtOAc/hexane (1:1) and solids were filtered off. Thefiltrate was washed with 0.5 M aqueous Na₂CO₃, dried (Na₂SO₄), andconcentrated in vacuo. The residue was purified by column chromatographyon silica to give 1.1 g (88%) of the N-Boc protected intermediate. Thismaterial was directly Al-Boc deprotected as described in Example 220,Step 2, to give 0.50 g (50% over two steps) of the title product as anoil. HRMS m/z calcd for C₂₂H₂₉N₅O₄ (M)⁺ 427.2220, found 427.2227.

Example 228

[1052]2-(1-Piperazinyl)-3-{2-[3-(tetrahydro-3-furanyloxy)phenoxy]ethoxy}pyrazine.

[1053] The title compound was prepared according to the procedure ofExample 227 starting from the product of Example 220, Step 1, and3-hdroxytetrahydrofuran. Yield 29% over two steps. HRMS m/z calcd forC₂₀H₂₆N₄O₄ (M)⁺ 386.1954, found 386.1963.

Example 229

[1054]2-(1-Piperazinyl)-3-{2-[3-(tetrahydro-3-furanylmethoxy)phenoxy]ethoxy}pyrazine.

[1055] The title compound was prepared according to the procedure ofExample 227 starting from the product of Example 220, Step 1, andtetrahydro-3-furanmethanol. Yield 48% over two steps. HRMS m/z calcd forC₂₁H₁₈N₄O₄ (M) 400.2111, found 400.2098.

Example 230

[1056]2-{[3-(2-{[3-(1-piperazinyl)-2-pyrazinyl]oxy}ethoxy)phenoxy]methyl}benzonitrile,Trifluoroacetate.

[1057] A suspension of the product obtained in Example 220, Step 1 (62mg, 0.15 mmol), 2-cyanobenzyl bromide (20 mg, 0.10 mmol) and polymersupported triazabicyclodecene (PTBD) (400 mg) in MeCN (8 mL) was shakenat room temperature for 48 h. The mixture was filtered and the filtrateconcentrated under reduced pressure to give the crude N-Boc protectedintermediate which still contained some unreacted phenol (by HPLC). Thismaterial was dissolved in MeCN (8 mL) then retreated with PTBD (300 mg)and shaken at room temperature overnight. The mixture was filtered andthe filtrate was concentrated under reduced pressure. The residue wasthen treated directly with a solution of 25% TFA in CH₂Cl₂ for 30 min atroom temperature. The reaction mixture was concentrated under reducedpressure to afford 32 mg (59%) of the title compound. MS m/z 432 (M+H)⁺.

Example 231

[1058] 2-{2-[3-(Benzyloxy)phenoxy]ethoxy}-3-(1-piperazinyl)pyrazine,Trifluoroacetate.

[1059] The title compound was prepared according to the procedure ofExample 230 starting from the product obtained in Example 220, Step 1(62 mg, 0.15 mmol), and benzyl-bromide (17 mg, 0.10 mmol) to give 14 mg(27%) of the title compound. MS m/z 407 (M+H)⁺.

Example 232

[1060]2-(1-Piperazinyl)-3-(2-{3-]2-(2-pyridinyl)ethoxy]phenoxy}ethoxy)pyrazine,Trifluoroacetate.

[1061] A solution of the product obtained in Example 220. Step 1 (208mg, 0.50 mmol) in CH₂Cl₂ (8 mL) was treated first with polymer supportedtriphenylphosphine (3.0 mmol/g) (200 mg; 0.60 mmol),2-(2-hydroxyethyl)pyridine (62 mg, 0.50 mmol) and then diethylazodicarboxylate (87 mg, 0.50 mmol). The reaction mixture was shaken atroom temperature for 3 h, then filtered to remove the solid support. Thefiltrate was concentrated under reduced pressure and the residue waspurified by chromatography on silica gel. Elution with diethyl ethergave the crude N-Boc-protected intermediate which was treated directlywith a solution of 25% TFA in CH₂Cl₂ for 30 min at room temperature. Thereaction mixture was concentrated under reduced pressure to afford 54 mg(20%) of the title compound. MS m/z 422 (M+H)⁺.

Example 233

[1062] 2-[(4-Methoxybenzyl)oxy]-3-(1-piperazinyl)pyrazine.

[1063] The title compound was prepared according to the procedure ofExample 90, Step 2, starting from 2-chloro-3-(1-piperazinyl)pyrazine(0.80 g, 4.0 mmol; from Example 90, Step 1) and 4-methoxybenzyl alcohol(0.88 g, 6.4 mmol). Oil; yield 72%. MS m/z 301 (M+H)⁺.

Example 234

[1064] 2-(1-Methyl-2-phenylethoxy)-3-(1-piperazinyl)pyrazine,Trifluoroacetate.

[1065] The title compound was prepared according to the procedure ofExample 90, Step 2, starting from 2-chloro-3-(1-piperazinyl)pyrazine(0.15 g, 0.75 mmol; from Example 90, Step 1) and 1-phenyl-2-propanol(163 mg, 1.2 mmol). MS m/z 299 (M+H)⁺. The crude product was purified byreverse phase preparative HPLC on a SymmetryPrep C₁₈ column (150×19 mm.7 μm), eluting with a gradient of 5% CH₃CN in 95% water to 95% CH₃CN in5% water (0.2% TFA buffer) to give gave 55 mg (18%) of the title productas a white solid. MS m/z 299 (M+H)⁺.

Example 235

[1066] 2-[2-(1-Naphthyl)ethoxy]-3-(1-piperazinyl)pyrazine,Trifluoroacetate.

[1067] The title compound was prepared according to the procedure ofExample 90. Step 2, starting from 2-chloro-3-(1-piperazinyl)pyrazine(0.50 g, 2.5 mmol; from Example 90, Step 1) and 1 naphthaleneethanol(0.69 g, 4.0 mmol). The crude product was purified by reverse phasepreparative HPLC on a Symmetry Prep C₁₈ column (150×19 mm, 7 μm),eluting with a gradient of 5% CH₃CN in 95% water to 95% C₁H₃CN in −5%water (0.2% TFA buffer) to give gave 290 mg (26%) of the title productas a white solid. MS 177/z 335 (M+H)⁺. Anal. (C₂₀H₂₂N₄O C₂HF₃O₂) C, H,N.

[1068] Preparation of Pharmaceutical Compositions

[1069] Example: Preparation of Tablets Ingredients mg/tablet 1. Activecompound 10.0 2. Cellulose, microcrystalline 57.0 3. Calcium hydrogenphosphate 15.0 4. Sodium starch glycolate 5.0 5. Silicon dioxide,colloidal 0.25 6. Magnesium stearate 0.75

[1070] The active ingredient 1 is mixed with ingredients 2, 3, 4 and 5for about 10 minutes. The magnesium stearate is then added, and theresultant mixture is mixed for about 5 minutes and compressed intotablet form with or without film-coating.

Pharmacological Tests

[1071] The ability of a compound of the invention to bind or act atspecific 5-HT receptor subtypes can be determined using in vitro and invivo assays known in the art. The biological activity of compoundsprepared in the Examples was tested using different tests.

[1072] Affinity Assay

[1073] The 5-HT_(2c) receptor affinity of compounds in the Examples wasdetermined in competition experiments, where the ability of eachcompound in serial dilution to displace ³H-labelled 5-HT, bound tomembranes prepared from a transfected HEK293 cell line stably expressingthe human 5-HT_(2c) receptor protein, was monitored by ScintillationProximity Assay technology. Non-specific binding was defined using 5 μMmianserin. Results obtained for exemplary compounds of the invention areillustrated in Table 1 below. Typically, the 5HT_(2c) receptor affinityvalues (K_(i), nM) were in the range of 1 nM to 1500 nM. TABLE 1Compound Ki (nM) Example 23 377 Example 57 24 Example 82 116 Example 125171 Example 122 45 Example 150 50 Example 151 185 Example 167 34 Example173 16 Example 183 10 Example 194 5 Example 231 12

[1074] Efficacy Assay

[1075] The agonist efficacy at the 5-HT_(2c) receptor of the compoundsin the Examples Was determined by the ability of each compound tomobilise intracellular calcium in transfected HEK293 cells, statblyexpressing the human 5-A1 U₂c receptor protein, using thecalcium-chelating fluorescent dye FLUO-3 (Sigma. St. Louis. Mo. U.S.A.).

[1076] Typically, the maximum responses of 5-HT_(2c) agonists were inthe range of 20-100% relative to the maximum response of 5-HT(serotonin) at a concentration of 1 μM.

[1077] Toxicity Tests

[1078] Acute toxicity studies in mice following oral administration of anumber of compounds in the Examples showed that mortality typicallyoccurred at doses between about 200 mg/kg body weight to about 450 mg/kgbody weight.

1. A compound of the general formula (I):

wherein Ar is aryl or heteroaryl which may be independently substitutedin one or more positions by C₁₋₆-alkyl, C₁₋₁₆-alkoxy, C₁₋₆-alkylthio,C₁₋₆-acyl, C₁₋₆-alkylsulphonyl, cyano, nitro, hydroxy, C₂₋₆-alkenyl,C₂₋₆-alkynyl, fluoromethyl, difluoromethyl, trifluoromethyl,difluoromethoxy, trifluoromethoxy, difluoromethylthio,trifluoromethylthio, halogen, —N(R₂)(R₃), aryl, aryloxy, arylthio,aryl-C₁₋₄alkyl, aryl-C₂₋₄-alkenyl, aryl-C₂₋₄-alkynyl, heterocyclyl,heterocyclyloxy, heterocyclylthio or heterocyclyl-C₁₋₄-alkyl, whereinany aryl and heterocyclyl residues as substituents or part ofsubstituents on aryl or heteroaryl in turn may be substituted in one ormore positions independently of each other by halogen, C₁₋₆-alkyl,C₁₋₆-alkoxy, C₁₋₆-alkylthio, C₁₋₆-acyl, C₁₋₆-alkylsulphonyl, nitro,trifluoromethyl, trifluoromethylthio, cyano, hydroxy, amino,C₁₋₆-alkylamino, di(C₁₋₆-alkyl)amino or C₁₋₆-acylamino; A is (i) —O—,—S—, —SO₂— or —NH—; (ii) a C₁₋₄-alkyl-substituted nitrogen atom, or(iii) a C₁₋₈-alkylene chain or a heteroalkylene chain having 2 to 8chain atoms, which optionally contains one or more unsaturations,wherein C₁₋₈-alkylene and heteroalkylene may be independentlysubstituted in one or more positions by C₁₋₄-alkyl or oxo, and whereintwo juxtaposed or spaced chain atoms in C₁₋₈-alkylene or heteroalkyleneoptionally are joined through an alkylene bridge having 1 to 5 chaincarbon atoms or a heteroalkylene bridge having 2 to 5 chain atoms, ortwo spaced chain atoms in C₁₋₈-alkylene or heteroalkylene optionally arejoined through a bridging bond, to form a saturated or partially orfully unsaturated carbocyclic or heterocyclic ring having 3 to 8 ringmembers; B is —C(R₄)(R₅)—, —OC(R₄)(R₅)—, —N(R₆)C(R₄)(R₅)—, —N(R₆)—, —O—,—S— or —SO₂—; R is C₃₋₈-cycloalkyl, aryl or heteroaryl, each of whichmay be substituted in one or more positions independently of each otherby C₁₋₆-alkyl, C₁₋₆-alkoxy, fluoro-C₁₋₆-alkoxy, 2,2,2-trifluoroethoxy,C₃₋₅-alkynyloxy, C₃₋₅-alkenyloxy, dimethylamino-C₁₋₆-alkoxy,methylamino-C₁₋₆-alkoxy, C₁₋₆-alkylthio, fluoromethyl, difluoromethyl,trifluoromethyl, fluoromethylthio, difluoromethoxy, difluoromethylthio,trifluoromethoxy, trifluoromethylthio, halogen, hydroxy, nitro, cyano,trifluoromethylsulphonyloxy, C₁₋₁₆-alkylsulphonamido, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₁₋₆-acyl, C₁₋₆-alkylcarbonyl-C₁₋₆-alkyl,C₁₋₆-alkylsulphonyl, C₁₋₆-alkylsulphonyloxy, C₁₋₆-alkoxy-C₁₋₆-alkyl,C₁₋₆-alkoxycarbonyl, C₁₋₆-alkoxycarbonyl-C₁₋₁₆-alkyl,C₁₋₁₆-acyloxy-C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, hydroxy-C₁₋₆-alkoxy,C₁₋₆-alkoxy-C₁₋₆-alkoxy, C₁₋₆-alkoxy-C₁₋₆-alkylthio,hydroxy-C₁₋₆-alkylthio, heteroaryl-C₁₋₆-alkylthio, aryl-C₁₋₆-alkylthio,C₁₋₆-alkoxy-C₁₋₆-alkylamino, N—(C₁₋₆-alkoxy-C₁₋₆-alkyl)-N-methylamino,C₃₋₆-cycloalkyl-C₁₋₆-alkoxy, aryl-C₁₋₆-alkoxy, heterocyclyl-C₁₋₆-alkoxy,C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyloxy, aryl, aryloxy, arylthio,arylsulphonyl, aryl-C₁₋₆-acyl, aryl-C₁₋₆-alkyl, aryl-C₂₋₆-alkenyl,aryl-C₂₋₆-alkynyl, heterocyclyl-C₁₋₆-alkyl, heterocyclyl-C₂₋₆-alkenyl,heterocyclyl-C₂₋₆-alkynyl, heterocyclyl, heterocyclyloxy,heterocyclylthio, heterocyclylsulphonyl, heterocyclylamino,heterocyclyl-C₁₋₆-acyl, —N(R₂)(R₃), —CON(R₇)(R₈) or, when R isoptionally substituted C₃₋₈-cycloalkyl, oxo, wherein any cycloalkyl,aryl and heterocyclyl residues as substituents on C₃₋₈-cycloalkyl, arylor heteroaryl or as part of substituents on C₃₋₈-cycloalkyl, aryl orheteroaryl in turn may be substituted in one or more positionsindependently of each other by C₁₋₄-alkyl, C₁₋₄-alkoxy,methanesulphonamido, C₁₋₄-alkylthio, C₁₋₄-alkylsulphonyl, C₁₋₄-acyl,heterocyclyl, heterocyclyloxy, heterocyclylthio, aryloxy, arylthio,fluoromethyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio,halogen, hydroxy, nitro, cyano, N(R₂)(R₃) or, for C₃₋₈-cycloalkyl andpartially or fully saturated heterocyclyl, oxo or hydroxy; R₁ is (i) asaturated or unsaturated azacyclic or aminoazacyclic ring, or asaturated diazacyclic or aminodiazacyclic ring, which has 4 to 7 ringmembers, or a saturated aminoazabicyclic, azabicyclic or diazabicyclicring which has 7 to 10 ring members, which mono- or bicyclic rings maybe mono- or disubstituted in one or more positions independently of eachother by, preferably bound to a carbon atom, C₁₋₄-alkyl, C₁₋₆-alkoxy,fluoromethyl, trifluoromethyl, difluoromethyl, oxo, hydroxymethyl ormethoxymethyl or —N(R₆)₂, or, preferably bound to a ring nitrogen atom,hydroxy, 2-hydroxyethyl or 2-cyanoethyl, or, bound to a ring nitrogenatom, C₁₋₆-acyl, C₁₋₄-alkoxycarbonyl or tetrahydropyran-2-yl, andwherein a saturated azacyclic ring may contain a further heteroatomselected from oxygen and sulphur; or (ii) a group—[C(R₄)(R₅)]_(x)N(R_(2a))(R_(3a)); R₂ and R₃ independently of each otherare hydrogen, C₁₋₆-alkyl, C₁₋₆-acyl, —CON(R₇)(R₈), aryl, heterocyclyl,aryl-C₁₋₆-alkyl, heterocyclyl-C₁₋₆-alkyl, aryl-C₁₋₆-acyl orheterocyclyl-C₁₋₆-acyl, wherein any aryl and heterocyclyl residues inturn may be substituted in one or more positions independently of eachother by halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, C₁₋₄-alkylthio,C₁₋₄-alkylsulphonyl, methanesulphonamido, nitro, cyano, hydroxy,trifluoromethyl, trifluoromethoxy, trifluoromethylthio or —N(R₂)(R₃); orR₂ and R₃ together with the nitrogen atom to which they are bound form asaturated heterocyclic ring having 4-7 ring members and optionallycontaining a further heteroatom, which ring may be substituted byC₁₋₆-alkyl, C₁₋₆-alkoxy, oxo or hydroxy; R_(2a) and R_(3a) independentlyof each other are hydrogen, methyl or ethyl, or R_(2a) and R_(3a)together with the nitrogen atom to which they are bound form apyrrolidine, piperazine or morpholine ring; R₄ and R₅ independently ofeach other, and independently on each substituted carbon atom, arehydrogen or C₁₋₆-alkyl; R₆ is hydrogen or C₁₋₆-alkyl; R₇ and R₈independently of each other are hydrogen, C₁₋₆-alkyl, aryl, heteroaryl,aryl-C₁₋₄ or heteroaryl-C₁₋₄-alkyl, wherein aryl and heteroaryl residuesin turn may be substituted in one or more positions independently ofeach other by halogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,C₁₋₆-alkylsulphonyl, methanesulphonamido, nitro, cyano, hydroxy,trifluoromethyl, trifluoromethoxy, trifluoromethylthio or —N(R₂)(R₃); orR₇ and R₈ together with the nitrogen atom to which they are bound form asaturated heterocyclic ring having 4-7 ring members and optionallycontaining a further heteroatom; n is 0 or 1, and x is 2, 3 or 4; withthe proviso that (i) when -A-R is phenoxy or phenylthio, then Ar isother than quinoxalinyl or pyridyl, and (ii) when A is ethenylene, thenAr is other than quinoxalinyl; and pharmaceutically acceptable salts,hydrates, geometrical isomers, tautomers, optical isomers, N-oxides andprodrug forms thereof.
 2. The compound according to claim 1, with thefurther proviso that when Ar is optionally substituted phenyl orpyridyl, then A is a group -Het-CH(R₆)—CH(R₆)-Het-, where each Hetindependently is selected from O, S and N(R₆), and R₆ is as defined inclaim
 1. 3. The compound according to claim 1, wherein A is aC₂₋₈-alkylene chain or a heteroalkylene chain having at least two chainatoms.
 4. The compound according to claim 1, wherein A is a group of thegeneral formula (II):

wherein R₉, R₁₀, R₁₁ and R₁₂ independently of each other, andindependently for each substituted carbon atom, are hydrogen, C₁₋₄-alkyl(preferably methyl), trifluoromethyl or oxo; X is —C(R₁₃)(R₁₄)—, —O—,—S—, —SO₂— or —N(R₁₅)—; Y is independently —C(R₁₆)(R₁₇)—, —O—, —S—,—SO₂— or —N(R₁₅)—; Z is independently —C(R₁₈)(R_(1g))-, —O—, —S—, —SO₂—or —N(R₁₅)—; R₁₃, R₁₄, R₁₆, R₁₇, R₁₈ and R₁₉, independently of eachother, and independently for each substituted carbon atom, are hydrogen,C₁₋₄-alkyl or trifluoromethyl or oxo; or two of R₁₃, R₁₄, R₁₆, R₁₇, R₁₈and R_(1g) together represent an interconnecting bond or an alkylenebridge of 1 to 5 chain carbon atoms or a heteroalkylene bridge of 2 to 5chain atoms to form, together with the atom(s) to which they are bound,a cyclic structure having 3-8 ring members; R₁₅ is hydrogen, C₁₋₄-alkylor C₁₋₆-acyl; o, p, q and r independently of each other are 0 to 3; andthe four broken lines independently of each other represent an optionalcarbon-carbon bond; with the provisos (i) that A does not contain twojuxtaposed heteroatoms O or S in an open chain, and (ii) that o, p, qand r together are not more than
 8. 5. The compound according to claim4, wherein A is a group -Het-CH(R₆)—CH(R₆)-Het-, where each Hetindependently is selected from O, S and N(R₆), and R₆ is as defined inclaim
 1. 6. The compound according to claim 5, wherein R₆ is hydrogen ormethyl, preferably hydrogen.
 7. The compound according to claim 5 or 6,wherein A is selected from the groups —O—CH₂—CH₂—O—, —S—CH₂—CH₂—O—,—O—CH₂—CH₂—S—, and —O—CH₂—CH₂—CH₂—, preferably —O—CH₂—CH₂—O.
 8. Thecompound according to claim 7, wherein A is —O—CH₂— and R is optionallysubstituted heteroaryl, e.g. 2,3-dihydro-1,4-benzodioxine,3,4-dihydro-2H-1,4-benzoxazine, or 2,3-dihydro-1,4-benzoxathiine,quinoline, benzofuran, 3,4-dihydro-2H-pyrido(3,2-b)-1,4-oxazine.
 9. Thecompound according to claim 1, wherein R is optionally substituted arylor heteroaryl.
 10. The compound according to claim 9, wherein R is anoptionally substituted phenyl, pyridine, isoquinoline, quinoline,quinoxaline, 2,3-dihydro-1,4-benzodioxine, benzoxazole,2,1,3-benzothiadiazole, coumarin, 3,4-dihydro-2H-1,4-benzoxazine orquinazoline, preferably a substituted (especially meta-substituted)phenyl ring, or an unsubstituted or substituted pyridine ring.
 11. Thecompound according to claim 1, wherein Ar is optionally substitutedpyrazine or phenyl.
 12. The compound according to claim 1, wherein Ar isunsubstituted or mono- or di-substituted.
 13. The compound according toclaim 1, wherein Ar is unsubstituted or mono- or independentlydi-substituted by C₁₋₄-alkyl, C₁₋₄-alkoxy, C₁₋₄-alkylthio,C₁₋₄-alkylsulphonyl, cyano, hydroxy, C₂₋₄-alkenyl, C₂₋₄-alkynyl,trifluoromethyl, trifluoromethylthio, halogen, amino, methylamino,dimetylamino, acetamido, aryl, aryloxy, arylthio, heterocyclyl,heterocyclyloxy, heterocyclylthio, wherein any aryl and heterocyclylresidues in turn may be substituted in one or more positionsindependently of each other by halogen, methyl, methoxy, methylthio,methylsulphonyl, nitro, trifluoromethyl, cyano, hydroxy, amino,methylamino and dimethylamino or acetamido.
 14. The compound accordingto claim 1, wherein B is —N(R₆)—, —O—, —S— or —SO₂—, where R₆ is asdefined in claim
 1. 15. The compound according to claim 1 which has thegeneral formula (Ia):

wherein: R₂₀ and R₂₁ independently of each other are hydrogen,C₁₋₄-alkyl, C₁₋₄-alkoxy, C₁₋₄-alkylthio, C₁₋₄-acyl, C₁₋₄-alkylsulphonyl,cyano, nitro, hydroxy, C₂₋₄-alkenyl, C₂₋₄-alkynyl, trifluoromethyl,trifluoromethoxy, trifluoromethylthio, halogen, amino, dimethylamino,methylamino, acetamido, aryl, aryloxy, arylthio, heterocyclyl,heterocyclyloxy or heterocyclylthio, wherein any aryl and heterocyclylresidues in turn may be substituted in one or more positionsindependently of each other by halogen, methyl, methoxy, methylthio,methylsulphonyl, nitro, cyano, hydroxy, trifluoromethyl, amino,methylamino, dimethylamino or acetamido; or R₂₀ and R₂₁ together withthe carbon atoms to which they are bound form a 5- or 6-memberedaromatic or heteroaromatic ring, which optionally is independentlysubstituted in one or more positions by halogen, methyl, methoxy,methylthio, methylsulphonyl, nitro, cyano, hydroxy, trifluoromethyl,trifluoromethylthio, amino, methylamino, dimethylamino or acetamido; m₁and m₂ are independently of each other 0 or 1; and A, B, R, R₁ and n areas defined in claim
 1. 16. The compound according to claim 15, wherein Ais as defined in claim 4, preferably as defined in claim 5, and morepreferably as defined in claim 6, especially as defined in claim
 7. 17.The compound according to claim 15, wherein n is 0, or n is 1 and B is—N(R₆)—, —O—, —S— or —SO₂—, where R₆ is as defined in claim
 1. 18. Thecompound according to claim 15, wherein R₂₀ and R₂₁ independently ofeach other are hydrogen, C₁₋₄-alkyl (preferably methyl), C₁₋₄-alkoxy(preferably methoxy), C₁₋₄-alkylthio (preferably methylthio), halogen,amino, methylamino, dimethylamino, acetamido, phenyl, phenoxy orphenylthio, wherein phenyl, phenoxy and phenylthio optionally may besubstituted in one or more positions (preferably mono- or disubstituted)independently of each other by halogen, methyl, methoxy, methylthio,cyano, hydroxy or trifluoromethyl, or R₂₀ and R₂₁ together with thecarbon atoms to which they are bound form a 5- or 6-membered aromatic orheteroaromatic ring, which optionally is independently substituted inone or more positions by halogen, methyl, methoxy, methylthio,methylsulphonyl, nitro, cyano, hydroxy, trifluoromethyl,trifluoromethylthio, amino, methylamino, dimethylamino or acetamido. 19.The compound according to claim 18, wherein R₂₀ and R₂₁ independently ofeach other are hydrogen, halogen or C₁₋₄-alkyl.
 20. The compoundaccording to claim 15, wherein R₂₀ and R₂₁ form a ring together with thering carbons to which they are bound.
 21. The compound according toclaim 20, wherein R₂₀ and R₂₁ together with the carbon atoms to whichthey are bound form thiophene to form a thieno[3,4-b]pyrazine ring,optionally mono- or di-substituted by halogen.
 22. The compoundaccording to claim 15, wherein m is
 0. 23. The compound according toclaim 1, wherein R₁ is piperazine, optionally substituted (preferably ata carbon atom, especially in 2-position) by C₁₋₄-alkyl, fluoromethyl,trifluoromethyl, hydroxymethyl or C₁₋₄-alkoxymethyl, preferablyC₁₋₄-alkyl.
 24. The compound according to claim 1, wherein n is
 0. 25.The compound according to claim 4, wherein o is
 2. 26. The compoundaccording to claim 4, wherein p is
 1. 27. The compound according toclaim 4, wherein q is
 0. 28. The compound according to claim 4, whereinr is
 0. 29. The compound according to claim 4, wherein at least one ofX, Y and Z is oxygen.
 30. The compound according to claim 4, wherein R₉to R₁₂ are hydrogen.
 31. The compound according to claim 1 which has thegeneral formula (Ib):

wherein: X₁ and Y₁ independently are —O—, —S— or —N(R₂₇)—; R_(a) is arylor heteroaryl optionally substituted as defined for R in claim 1; R₂₀and R₂₁ are as defined in claim 11; R₂₂ is hydrogen, hydroxy,C₁₋₄-alkyl, C₃₋₄-alkenyl, C₁₋₄-acyl, C₁₋₄-alkoxycarbonyl,2-hydroxyethyl, 2-cyanoethyl or tetrahydropyran-2-yl; R₂₃ and R₂₄independently of each other are hydrogen, C₁₋₄-alkyl, hydroxymethyl,C₁₋₄-alkoxymethyl or fluoromethyl; R₂₅ is hydrogen or C₁₋₄-alkyl; R₂₆ ishydrogen, C₁₋₄-alkyl or is linked to a carbon atom in R_(a) adjacent tothe atom binding to Y₁ to form a 5- or 6-membered ring which may containan additional heteroatom, R₂₇ is hydrogen or C₁₋₄-alkyl, preferablymethyl or ethyl; and y and z independently of each other are 1 or
 2. 32.The compound according to claim 31, wherein R₂₀ and R₂₁ are as definedin claim
 18. 33. The compound according to claim 31, wherein X₁ and Y₁both are —O—.
 34. The compound according to claim 31 wherein X₁ is —S—and Y₁ is —O—.
 35. The compound according to claim 31, wherein X₁ is —O—and Y₁ is —S—.
 36. The compound according to claim 31, wherein X₁ and Y₁both are —S—.
 37. The compound according to claim 31, wherein R₂₂ ishydrogen.
 38. The compound according to claim 31, wherein R₂₃ is methyl,z is 1 and R₂₄ is hydrogen, preferably in (R)-configuration.
 39. Thecompound according to claim 31, wherein R₂₅ is hydrogen and R₂₆ ismethyl.
 40. The compound according to claim 31, wherein R₂₅ is hydrogen.41-53. (Canceled).
 54. A pharmaceutical composition comprising acompound according to claim 1 to as an active ingredient, together witha pharmacologically and pharmaceutically acceptable carrier.
 55. Amethod for the prophylaxis or treatment of a serotonin-related,especially 5-HT₂ receptor-related, disease in a human being or in ananimal, particularly a disease related to the 5-HT2_(c) receptor,especially selected from eating disorders, especially obesity, memorydisorders, schizophrenia, mood disorders, anxiety disorders, pain,sexual dysfunctions, and urinary disorders, which method comprisesadministering an effective amount of a compound according to claim 1 toa subject suffering from said disease.
 56. A method for modulating 5HT2receptor function, especially 5HT2_(c) receptor function, comprisingcontacting the receptor with an effective inhibitory amount of acompound according to claim
 1. 57. A process for the preparation of acompound of the formula (I) in claim 1, which process comprises: a) forthe preparation of a compound of formula (I) above in which A is boundto Ar via an O, S or N atom in A, and (i) n=0 and R₁ is a saturatedaminoazacyclic, aminodiazacyclic, diazacyclic or diazabicyclic residue,or (ii) n=1, B is —N(R₆)— or —N(R₆)C(R₄)(R₅)—, wherein R₄, R₅ and R₆ areas defined in claim 1, and R₁ is a saturated or unsaturated azacyclic,or a saturated azabicyclic, residue, reacting a compound of thestructural formula (III):

wherein Ar is as defined in claim 1 and Hal is halogen, with a compoundR-A′-X′-H or its corresponding anion where X′ is —O—, —S— or —N(R₁₅)—,A′ is C₁₋₈-alkylene wherein the carbon chain may be interrupted by oneor more heteroatoms and which may have a terminal heteroatom binding toR, said heteroatoms being selected from N, O and S, and R is as definedin claim 1 and R₁₅ is as defined in claim 4, to produce a compound ofthe formula (IV):

wherein Ar, X′, A′, R and Hal are as defined above, and subsequentlyreacting the compound of formula (IV) with an appropriate amine toproduce the compound of formula (I); or b) for the preparation of acompound of formula (I) in which n=1, B is oxygen or sulphur and R₁ is asaturated azacyclic or azabicyclic residue, or a group—[C(R₄)(R₅)]_(x)N(R_(2a))(R_(3a)), wherein R₂, R₃, R₄, R₅ and x are asdefined in claim 1, reacting a compound of formula (IV) above with acorresponding hydroxy- or mercapto-substituted azacyclic or azabicycliccompound, or with a compound HO—R₁ or HS—R₁, where R₁ is—[C(R₄)(R₅)]_(x)N(R_(2a))(R_(3a)), wherein R₂, R₃, R₄, R₅ and x are asdefined above, to produce the compound of formula (I); or c) for thepreparation of a compound of formula (I), wherein A is bound to R via anoxygen or sulphur atom in A, reacting a compound of formula (V):

wherein Ar, R₁, B and n are as defined above, A″ is C₁-alkylene whereinthe carbon chain may be interrupted by one or more heteroatoms and whichmay have a terminal heteroatom bound to Ar, said heteroatoms beingselected from N, O and S, and L is a hydroxy, thiol or a leaving groupwith a compound R—OH or R—SH, where R is as defined in claim 1, toproduce the compound of formula (D); or d) for the preparation of acompound of formula (I), in which A is bound to Ar via an O, S or N atomin A, and wherein n=0, or n=1 and B is oxygen, nitrogen, sulphur or—N(R₆)C(R₄)(R₅)—, wherein R₄, R₅ and R₇ are as defined in claim 1,reacting a compound of formula (III) above with an appropriate amine, oran appropriate hydroxy- or mercapto-substituted compound to produce acompound of formula (VI):

wherein Ar, B, R₁, Hal and n are as defined in claim 1, and subsequentlyreacting the compound of formula (VI) with a compound R-A′-X′-H or itscorresponding anion, where X′ is —O—, —S— or —N(R₁₅)—, A′ isC₁₋₈-alkylene wherein the carbon chain may be interrupted by one or moreheteroatoms and which may have a terminal heteroatom binding to R, saidheteroatoms being selected from N, O and S, and R is as defined in claim1 and R₁₅ is as defined in claim 4, to produce the compound of theformula (I); optionally converting a resulting compound of formula (I)to another compound of formula (I); and, if desired, separating aracemate obtained into optical isomers and/or forming an acid additionsalt with an organic or inorganic acid.
 58. The method of claim 55,wherein the mood disorders comprises major depression and bipolardepression including both mild and bipolar disorder, and seasonalaffective disorder (SAD).
 59. The method of claim 55, wherein theanxiety disorder comprises situational anxiety, generalized anxietydisorder, primary anxiety disorders and secondary anxiety disorders.